diff --git a/.github/workflows/deploy-latest.yml b/.github/workflows/deploy-latest.yml
index 4f67b030..6907b438 100644
--- a/.github/workflows/deploy-latest.yml
+++ b/.github/workflows/deploy-latest.yml
@@ -25,7 +25,7 @@ jobs:
       name: Configure pip caching
       with:
         path: ~/.cache/pip
-        key: ${{ runner.os }}-pip-${{ hashFiles('**/setup.py') }}
+        key: ${{ runner.os }}-pip-${{ hashFiles('**/pyproject.toml') }}
         restore-keys: |
           ${{ runner.os }}-pip-
     - name: Install Python dependencies
diff --git a/.github/workflows/publish.yml b/.github/workflows/publish.yml
index 5acb4899..14bfaded 100644
--- a/.github/workflows/publish.yml
+++ b/.github/workflows/publish.yml
@@ -20,7 +20,7 @@ jobs:
       with:
         python-version: ${{ matrix.python-version }}
         cache: pip
-        cache-dependency-path: setup.py
+        cache-dependency-path: pyproject.toml
     - name: Install dependencies
       run: |
         pip install -e '.[test]'
@@ -41,7 +41,7 @@ jobs:
       with:
         python-version: '3.13'
         cache: pip
-        cache-dependency-path: setup.py
+        cache-dependency-path: pyproject.toml
     - name: Install dependencies
       run: |
         pip install setuptools wheel build
@@ -62,7 +62,7 @@ jobs:
       with:
         python-version: '3.10'
         cache: pip
-        cache-dependency-path: setup.py
+        cache-dependency-path: pyproject.toml
     - name: Install dependencies
       run: |
         python -m pip install -e .[docs]
diff --git a/.github/workflows/spellcheck.yml b/.github/workflows/spellcheck.yml
index 8a47fd2d..7c5370ce 100644
--- a/.github/workflows/spellcheck.yml
+++ b/.github/workflows/spellcheck.yml
@@ -15,7 +15,7 @@ jobs:
       with:
         python-version: '3.11'
         cache: 'pip'
-        cache-dependency-path: '**/setup.py'
+        cache-dependency-path: '**/pyproject.toml'
     - name: Install dependencies
       run: |
         pip install -e '.[docs]'
diff --git a/.github/workflows/test-coverage.yml b/.github/workflows/test-coverage.yml
index 22a69150..8d73b64d 100644
--- a/.github/workflows/test-coverage.yml
+++ b/.github/workflows/test-coverage.yml
@@ -21,7 +21,7 @@ jobs:
       with:
         python-version: '3.12'
         cache: 'pip'
-        cache-dependency-path: '**/setup.py'
+        cache-dependency-path: '**/pyproject.toml'
     - name: Install Python dependencies
       run: |
         python -m pip install --upgrade pip
diff --git a/.github/workflows/test-pyodide.yml b/.github/workflows/test-pyodide.yml
index 7357b30c..b490a9bf 100644
--- a/.github/workflows/test-pyodide.yml
+++ b/.github/workflows/test-pyodide.yml
@@ -18,7 +18,7 @@ jobs:
       with:
         python-version: "3.10"
         cache: 'pip'
-        cache-dependency-path: '**/setup.py'
+        cache-dependency-path: '**/pyproject.toml'
     - name: Cache Playwright browsers
       uses: actions/cache@v4
       with:
diff --git a/.github/workflows/test-sqlite-support.yml b/.github/workflows/test-sqlite-support.yml
index 698aec8a..76ea138a 100644
--- a/.github/workflows/test-sqlite-support.yml
+++ b/.github/workflows/test-sqlite-support.yml
@@ -32,7 +32,7 @@ jobs:
         python-version: ${{ matrix.python-version }}
         allow-prereleases: true
         cache: pip
-        cache-dependency-path: setup.py
+        cache-dependency-path: pyproject.toml
     - name: Set up SQLite ${{ matrix.sqlite-version }}
       uses: asg017/sqlite-versions@71ea0de37ae739c33e447af91ba71dda8fcf22e6
       with:
diff --git a/.github/workflows/test.yml b/.github/workflows/test.yml
index e6d67b5c..1e5e03d2 100644
--- a/.github/workflows/test.yml
+++ b/.github/workflows/test.yml
@@ -19,7 +19,7 @@ jobs:
         python-version: ${{ matrix.python-version }}
         allow-prereleases: true
         cache: pip
-        cache-dependency-path: setup.py
+        cache-dependency-path: pyproject.toml
     - name: Build extension for --load-extension test
       run: |-
         (cd tests && gcc ext.c -fPIC -shared -o ext.so)
diff --git a/.gitignore b/.gitignore
index 277ff653..70e6bbeb 100644
--- a/.gitignore
+++ b/.gitignore
@@ -5,6 +5,9 @@ scratchpad
 
 .vscode
 
+uv.lock
+data.db
+
 # We don't use Pipfile, so ignore them
 Pipfile
 Pipfile.lock
@@ -123,4 +126,4 @@ node_modules
 # include it in source control.
 tests/*.dylib
 tests/*.so
-tests/*.dll
\ No newline at end of file
+tests/*.dll
diff --git a/Justfile b/Justfile
index 3e7e467a..8e4d6066 100644
--- a/Justfile
+++ b/Justfile
@@ -5,39 +5,39 @@ export DATASETTE_SECRET := "not_a_secret"
 
 # Setup project
 @init:
-  pipenv run pip install -e '.[test,docs]'
+  uv sync --extra test --extra docs
 
 # Run pytest with supplied options
-@test *options:
-  pipenv run pytest {{options}}
+@test *options: init
+  uv run pytest -n auto {{options}}
 
 @codespell:
-  pipenv run codespell README.md --ignore-words docs/codespell-ignore-words.txt
-  pipenv run codespell docs/*.rst --ignore-words docs/codespell-ignore-words.txt
-  pipenv run codespell datasette -S datasette/static --ignore-words docs/codespell-ignore-words.txt
-  pipenv run codespell tests --ignore-words docs/codespell-ignore-words.txt
+  uv run codespell README.md --ignore-words docs/codespell-ignore-words.txt
+  uv run codespell docs/*.rst --ignore-words docs/codespell-ignore-words.txt
+  uv run codespell datasette -S datasette/static --ignore-words docs/codespell-ignore-words.txt
+  uv run codespell tests --ignore-words docs/codespell-ignore-words.txt
 
 # Run linters: black, flake8, mypy, cog
 @lint: codespell
-  pipenv run black . --check
-  pipenv run flake8
-  pipenv run cog --check README.md docs/*.rst
+  uv run black . --check
+  uv run flake8
+  uv run cog --check README.md docs/*.rst
 
 # Rebuild docs with cog
 @cog:
-  pipenv run cog -r README.md docs/*.rst
+  uv run cog -r README.md docs/*.rst
 
 # Serve live docs on localhost:8000
 @docs: cog blacken-docs
-  cd docs && pipenv run make livehtml
+  cd docs && uv run make livehtml
 
 # Apply Black
 @black:
-  pipenv run black .
+  uv run black .
 
 # Apply blacken-docs
 @blacken-docs:
-  pipenv run blacken-docs -l 60 docs/*.rst
+  uv run blacken-docs -l 60 docs/*.rst
 
 # Apply prettier
 @prettier:
@@ -46,7 +46,7 @@ export DATASETTE_SECRET := "not_a_secret"
 # Format code with both black and prettier
 @format: black prettier blacken-docs
 
-@serve:
-  pipenv run sqlite-utils create-database data.db
-  pipenv run sqlite-utils create-table data.db docs id integer title text --pk id --ignore
-  pipenv run python -m datasette data.db --root --reload
+@serve *options:
+  uv run sqlite-utils create-database data.db
+  uv run sqlite-utils create-table data.db docs id integer title text --pk id --ignore
+  uv run python -m datasette data.db --root --reload {{options}}
diff --git a/docs/contributing.rst b/docs/contributing.rst
index 12c8d477..4771aa11 100644
--- a/docs/contributing.rst
+++ b/docs/contributing.rst
@@ -42,7 +42,7 @@ The next step is to create a virtual environment for your project and use it to
     # Install Datasette and its testing dependencies
     python3 -m pip install -e '.[test]'
 
-That last line does most of the work: ``pip install -e`` means "install this package in a way that allows me to edit the source code in place". The ``.[test]`` option means "use the setup.py in this directory and install the optional testing dependencies as well".
+That last line does most of the work: ``pip install -e`` means "install this package in a way that allows me to edit the source code in place". The ``.[test]`` option means "install the optional testing dependencies as well".
 
 .. _contributing_running_tests:
 
@@ -160,7 +160,7 @@ If any of your code does not conform to Black you can run this to automatically
 
 ::
 
-    reformatted ../datasette/setup.py
+    reformatted ../datasette/app.py
     All done! ✨ 🍰 ✨
     1 file reformatted, 94 files left unchanged.
 
diff --git a/docs/plugin_hooks.rst b/docs/plugin_hooks.rst
index b1615e27..a06d3b4c 100644
--- a/docs/plugin_hooks.rst
+++ b/docs/plugin_hooks.rst
@@ -691,7 +691,7 @@ Help text (from the docstring for the function plus any defined Click arguments
 
 Plugins can register multiple commands by making multiple calls to the ``@cli.command()`` decorator. Consult the `Click documentation <https://click.palletsprojects.com/>`__ for full details on how to build a CLI command, including how to define arguments and options.
 
-Note that ``register_commands()`` plugins cannot used with the :ref:`--plugins-dir mechanism <writing_plugins_one_off>` - they need to be installed into the same virtual environment as Datasette using ``pip install``. Provided it has a ``setup.py`` file (see :ref:`writing_plugins_packaging`) you can run ``pip install`` directly against the directory in which you are developing your plugin like so::
+Note that ``register_commands()`` plugins cannot used with the :ref:`--plugins-dir mechanism <writing_plugins_one_off>` - they need to be installed into the same virtual environment as Datasette using ``pip install``. Provided it has a ``pyproject.toml`` file (see :ref:`writing_plugins_packaging`) you can run ``pip install`` directly against the directory in which you are developing your plugin like so::
 
     pip install -e path/to/my/datasette-plugin
 
diff --git a/docs/testing_plugins.rst b/docs/testing_plugins.rst
index f1363fb4..e4fad500 100644
--- a/docs/testing_plugins.rst
+++ b/docs/testing_plugins.rst
@@ -33,16 +33,16 @@ You can install these packages like so::
 
     pip install pytest pytest-asyncio
 
-If you are building an installable package you can add them as test dependencies to your ``setup.py`` module like this:
+If you are building an installable package you can add them as test dependencies to your ``pyproject.toml`` file like this:
 
-.. code-block:: python
+.. code-block:: toml
 
-    setup(
-        name="datasette-my-plugin",
-        # ...
-        extras_require={"test": ["pytest", "pytest-asyncio"]},
-        tests_require=["datasette-my-plugin[test]"],
-    )
+    [project]
+    name = "datasette-my-plugin"
+    # ...
+
+    [project.optional-dependencies]
+    test = ["pytest", "pytest-asyncio"]
 
 You can then install the test dependencies like so::
 
diff --git a/pyproject.toml b/pyproject.toml
new file mode 100644
index 00000000..1536c09b
--- /dev/null
+++ b/pyproject.toml
@@ -0,0 +1,93 @@
+[project]
+name = "datasette"
+dynamic = ["version"]
+description = "An open source multi-tool for exploring and publishing data"
+readme = { file = "README.md", content-type = "text/markdown" }
+authors = [
+    { name = "Simon Willison" },
+]
+license = "Apache-2.0"
+requires-python = ">=3.10"
+classifiers = [
+    "Development Status :: 4 - Beta",
+    "Framework :: Datasette",
+    "Intended Audience :: Developers",
+    "Intended Audience :: Science/Research",
+    "Intended Audience :: End Users/Desktop",
+    "Topic :: Database",
+    "Programming Language :: Python :: 3.10",
+    "Programming Language :: Python :: 3.11",
+    "Programming Language :: Python :: 3.12",
+    "Programming Language :: Python :: 3.13",
+    "Programming Language :: Python :: 3.14",
+]
+
+dependencies = [
+    "asgiref>=3.2.10",
+    "click>=7.1.1",
+    "click-default-group>=1.2.3",
+    "Jinja2>=2.10.3",
+    "hupper>=1.9",
+    "httpx>=0.20",
+    "pluggy>=1.0",
+    "uvicorn>=0.11",
+    "aiofiles>=0.4",
+    "janus>=0.6.2",
+    "asgi-csrf>=0.10",
+    "PyYAML>=5.3",
+    "mergedeep>=1.1.1",
+    "itsdangerous>=1.1",
+    "sqlite-utils>=3.30",
+    "asyncinject>=0.6.1",
+    "setuptools",
+    "pip",
+]
+
+[project.urls]
+Homepage = "https://datasette.io/"
+Documentation = "https://docs.datasette.io/en/stable/"
+Changelog = "https://docs.datasette.io/en/stable/changelog.html"
+"Live demo" = "https://latest.datasette.io/"
+"Source code" = "https://github.com/simonw/datasette"
+Issues = "https://github.com/simonw/datasette/issues"
+CI = "https://github.com/simonw/datasette/actions?query=workflow%3ATest"
+
+[project.scripts]
+datasette = "datasette.cli:cli"
+
+[project.optional-dependencies]
+docs = [
+    "Sphinx==7.4.7",
+    "furo==2025.9.25",
+    "sphinx-autobuild",
+    "codespell>=2.2.5",
+    "blacken-docs",
+    "sphinx-copybutton",
+    "sphinx-inline-tabs",
+    "ruamel.yaml",
+]
+test = [
+    "pytest>=5.2.2",
+    "pytest-xdist>=2.2.1",
+    "pytest-asyncio>=1.2.0",
+    "beautifulsoup4>=4.8.1",
+    "black==25.9.0",
+    "blacken-docs==1.20.0",
+    "pytest-timeout>=1.4.2",
+    "trustme>=0.7",
+    "cogapp>=3.3.0",
+]
+rich = ["rich"]
+
+[build-system]
+requires = ["setuptools"]
+build-backend = "setuptools.build_meta"
+
+[tool.setuptools.packages.find]
+include = ["datasette*"]
+
+[tool.setuptools.package-data]
+datasette = ["templates/*.html"]
+
+[tool.setuptools.dynamic]
+version = {attr = "datasette.version.__version__"}
diff --git a/setup.py b/setup.py
deleted file mode 100644
index 7b7a7747..00000000
--- a/setup.py
+++ /dev/null
@@ -1,107 +0,0 @@
-from setuptools import setup, find_packages
-import os
-
-
-def get_long_description():
-    with open(
-        os.path.join(os.path.dirname(os.path.abspath(__file__)), "README.md"),
-        encoding="utf8",
-    ) as fp:
-        return fp.read()
-
-
-def get_version():
-    path = os.path.join(
-        os.path.dirname(os.path.abspath(__file__)), "datasette", "version.py"
-    )
-    g = {}
-    with open(path) as fp:
-        exec(fp.read(), g)
-    return g["__version__"]
-
-
-setup(
-    name="datasette",
-    version=get_version(),
-    description="An open source multi-tool for exploring and publishing data",
-    long_description=get_long_description(),
-    long_description_content_type="text/markdown",
-    author="Simon Willison",
-    license="Apache License, Version 2.0",
-    url="https://datasette.io/",
-    project_urls={
-        "Documentation": "https://docs.datasette.io/en/stable/",
-        "Changelog": "https://docs.datasette.io/en/stable/changelog.html",
-        "Live demo": "https://latest.datasette.io/",
-        "Source code": "https://github.com/simonw/datasette",
-        "Issues": "https://github.com/simonw/datasette/issues",
-        "CI": "https://github.com/simonw/datasette/actions?query=workflow%3ATest",
-    },
-    packages=find_packages(exclude=("tests",)),
-    package_data={"datasette": ["templates/*.html"]},
-    include_package_data=True,
-    python_requires=">=3.10",
-    install_requires=[
-        "asgiref>=3.2.10",
-        "click>=7.1.1",
-        "click-default-group>=1.2.3",
-        "Jinja2>=2.10.3",
-        "hupper>=1.9",
-        "httpx>=0.20",
-        'importlib_metadata>=4.6; python_version < "3.10"',
-        "pluggy>=1.0",
-        "uvicorn>=0.11",
-        "aiofiles>=0.4",
-        "janus>=0.6.2",
-        "asgi-csrf>=0.10",
-        "PyYAML>=5.3",
-        "mergedeep>=1.1.1",
-        "itsdangerous>=1.1",
-        "sqlite-utils>=3.30",
-        "asyncinject>=0.6.1",
-        "setuptools",
-        "pip",
-    ],
-    entry_points="""
-        [console_scripts]
-        datasette=datasette.cli:cli
-    """,
-    extras_require={
-        "docs": [
-            "Sphinx==7.4.7",
-            "furo==2025.9.25",
-            "sphinx-autobuild",
-            "codespell>=2.2.5",
-            "blacken-docs",
-            "sphinx-copybutton",
-            "sphinx-inline-tabs",
-            "ruamel.yaml",
-        ],
-        "test": [
-            "pytest>=5.2.2",
-            "pytest-xdist>=2.2.1",
-            "pytest-asyncio>=1.2.0",
-            "beautifulsoup4>=4.8.1",
-            "black==25.9.0",
-            "blacken-docs==1.20.0",
-            "pytest-timeout>=1.4.2",
-            "trustme>=0.7",
-            "cogapp>=3.3.0",
-        ],
-        "rich": ["rich"],
-    },
-    classifiers=[
-        "Development Status :: 4 - Beta",
-        "Framework :: Datasette",
-        "Intended Audience :: Developers",
-        "Intended Audience :: Science/Research",
-        "Intended Audience :: End Users/Desktop",
-        "Topic :: Database",
-        "License :: OSI Approved :: Apache Software License",
-        "Programming Language :: Python :: 3.14",
-        "Programming Language :: Python :: 3.13",
-        "Programming Language :: Python :: 3.12",
-        "Programming Language :: Python :: 3.11",
-        "Programming Language :: Python :: 3.10",
-    ],
-)
diff --git a/tests/conftest.py b/tests/conftest.py
index 4749fe6a..31c45ed3 100644
--- a/tests/conftest.py
+++ b/tests/conftest.py
@@ -42,7 +42,9 @@ def wait_until_responds(url, timeout=5.0, client=httpx, **kwargs):
 @pytest_asyncio.fixture
 async def ds_client():
     from datasette.app import Datasette
+    from datasette.database import Database
     from .fixtures import CONFIG, METADATA, PLUGINS_DIR
+    import secrets
 
     global _ds_client
     if _ds_client is not None:
@@ -63,7 +65,10 @@ async def ds_client():
     )
     from .fixtures import TABLES, TABLE_PARAMETERIZED_SQL
 
-    db = ds.add_memory_database("fixtures")
+    # Use a unique memory_name to avoid collisions between different
+    # Datasette instances in the same process, but use "fixtures" for routing
+    unique_memory_name = f"fixtures_{secrets.token_hex(8)}"
+    db = ds.add_database(Database(ds, memory_name=unique_memory_name), name="fixtures")
     ds.remove_database("_memory")
 
     def prepare(conn):