diff --git a/.github/workflows/docs.yml b/.github/workflows/docs.yml
index 0083daac64..154e092f7a 100644
--- a/.github/workflows/docs.yml
+++ b/.github/workflows/docs.yml
@@ -53,7 +53,7 @@ jobs:
 
       - name: Build C module
         if: env.MAKE_TARGET
-        run: make $MAKE_TARGET
+        run: cd python && meson setup build && meson compile -C build
 
       - name: Build Docs
         run: |
diff --git a/.github/workflows/tests.yml b/.github/workflows/tests.yml
index 30b1c1b5f3..8bc89db5b8 100644
--- a/.github/workflows/tests.yml
+++ b/.github/workflows/tests.yml
@@ -74,11 +74,12 @@ jobs:
         working-directory: python
         if: matrix.os == 'windows-latest'
         run: |
-          rm -r lib
-          mkdir lib
-          cp -r --dereference ../c/subprojects lib/.
-          cp -r --dereference ../c/tskit lib/.
-          cp ../c/tskit.h lib/.
+          rm subprojects/libtskit
+          mkdir -p subprojects/libtskit
+          cp -r --dereference ../c/subprojects subprojects/libtskit/.
+          cp -r --dereference ../c/tskit subprojects/libtskit/.
+          cp ../c/meson.build subprojects/libtskit/
+          cp ../c/VERSION.txt subprojects/libtskit/
 
       - name: Fix windows .profile
         if: steps.cache.outputs.cache-hit != 'true' && matrix.os == 'windows-latest'
@@ -104,7 +105,13 @@ jobs:
         run: |
           source ~/.profile
           conda activate anaconda-client-env
-          python setup.py build_ext --inplace
+          if [[ "${{ matrix.os }}" == "windows-latest" ]]; then
+            meson setup build --vsenv --backend=vs
+          else
+            meson setup build
+          fi
+          meson compile -C build
+          mv build/_tskit*.so .
 
       - name: Minidom test
         working-directory: python
@@ -165,7 +172,9 @@ jobs:
       - name: Build module
         working-directory: python
         run: |
-          python setup.py build_ext --inplace
+          meson setup build
+          meson compile -C build
+          mv build/_tskit*.so .
 
       - name: Run tests with numpy 1.x
         working-directory: python
diff --git a/python/_tskitmodule.c b/python/_tskitmodule.c
index cab445e5d0..951d9b9f33 100644
--- a/python/_tskitmodule.c
+++ b/python/_tskitmodule.c
@@ -14714,7 +14714,7 @@ static struct PyModuleDef tskitmodule = {
     .m_methods = tskit_methods,
 };
 
-PyObject *
+PyMODINIT_FUNC
 PyInit__tskit(void)
 {
     PyObject *module;
diff --git a/python/flake.lock b/python/flake.lock
new file mode 100644
index 0000000000..0230c28820
--- /dev/null
+++ b/python/flake.lock
@@ -0,0 +1,27 @@
+{
+  "nodes": {
+    "nixpkgs": {
+      "locked": {
+        "lastModified": 1753115646,
+        "narHash": "sha256-yLuz5cz5Z+sn8DRAfNkrd2Z1cV6DaYO9JMrEz4KZo/c=",
+        "owner": "NixOS",
+        "repo": "nixpkgs",
+        "rev": "92c2e04a475523e723c67ef872d8037379073681",
+        "type": "github"
+      },
+      "original": {
+        "owner": "NixOS",
+        "ref": "nixos-25.05",
+        "repo": "nixpkgs",
+        "type": "github"
+      }
+    },
+    "root": {
+      "inputs": {
+        "nixpkgs": "nixpkgs"
+      }
+    }
+  },
+  "root": "root",
+  "version": 7
+}
diff --git a/python/flake.nix b/python/flake.nix
new file mode 100644
index 0000000000..81bdc0fd0e
--- /dev/null
+++ b/python/flake.nix
@@ -0,0 +1,26 @@
+{
+  inputs.nixpkgs.url = "github:NixOS/nixpkgs/nixos-25.05";
+  outputs =
+    { self, nixpkgs }@inputs:
+    let
+      system = "x86_64-linux";
+      pkgs = import inputs.nixpkgs { inherit system; };
+    in
+    {
+      devShells.${system}.default =
+        (pkgs.buildFHSEnv {
+          name = "python";
+          targetPkgs = pkgs: [
+            pkgs.gcc
+	    pkgs.gsl
+	    pkgs.gsl.dev
+            pkgs.libz
+	    pkgs.meson
+	    pkgs.ninja
+            pkgs.pkg-config
+            pkgs.python313Full
+          ];
+          runScript = "fish";
+        }).env;
+    };
+}
diff --git a/python/lib b/python/lib
deleted file mode 120000
index 9e8cf0c2ee..0000000000
--- a/python/lib
+++ /dev/null
@@ -1 +0,0 @@
-../c/
\ No newline at end of file
diff --git a/python/meson.build b/python/meson.build
new file mode 100644
index 0000000000..329479878a
--- /dev/null
+++ b/python/meson.build
@@ -0,0 +1,29 @@
+project(
+  'tskit', 'c',
+  version: run_command(['tskit' / '_version.py'], check: true).stdout().strip(),
+  default_options: ['c_std=c99', 'cpp_std=c++11']
+)
+
+subdir('tskit')
+py = import('python').find_installation(pure: false)
+py.install_sources(src, subdir: 'tskit')
+
+deps = [
+  subproject(
+    'libtskit', default_options: ['werror=false']
+  ).get_variable('tskit_dep'),
+  declare_dependency(
+    include_directories: run_command(
+      py, '-c', 'import numpy;print(numpy.get_include())',
+      check: true
+    ).stdout().strip()
+  )
+]
+
+py.extension_module(
+  '_tskit',
+  '_tskitmodule.c',
+  dependencies: deps,
+  include_directories: 'lwt_interface',
+  install: true,
+)
diff --git a/python/pyproject.toml b/python/pyproject.toml
index 80b9cc1f78..3922e80a76 100644
--- a/python/pyproject.toml
+++ b/python/pyproject.toml
@@ -1,6 +1,10 @@
 [build-system]
-requires = ["setuptools>=45", "wheel", "numpy>=2.0"]
-build-backend = "setuptools.build_meta"
+requires = ["meson-python", "numpy>=2.0"]
+build-backend = "mesonpy"
+
+[tool.meson-python.args]
+setup = ["--default-library=static"]
+install = ["--skip-subprojects"]
 
 [project]
 name = "tskit"
@@ -56,12 +60,6 @@ GitHub = "https://github.com/tskit-dev/tskit/"
 [project.scripts]
 tskit = "tskit.cli:tskit_main"
 
-[tool.setuptools]
-packages = ["tskit"]
-
-[tool.setuptools.dynamic]
-version = {attr = "tskit._version.tskit_version"}
-
 [tool.pytest.ini_options]
 addopts = "-n 4"
 testpaths = ["tests"]
diff --git a/python/requirements/CI-complete/requirements.txt b/python/requirements/CI-complete/requirements.txt
index 8920fa33ca..2b6e281a87 100644
--- a/python/requirements/CI-complete/requirements.txt
+++ b/python/requirements/CI-complete/requirements.txt
@@ -1,3 +1,5 @@
+meson==1.8.2
+ninja==1.11.1.4
 biopython==1.85
 coverage==7.7.0
 dendropy==5.0.1
diff --git a/python/requirements/CI-docs/requirements.txt b/python/requirements/CI-docs/requirements.txt
index 09877a41dd..3b4c746f10 100644
--- a/python/requirements/CI-docs/requirements.txt
+++ b/python/requirements/CI-docs/requirements.txt
@@ -1,3 +1,5 @@
+meson==1.8.2
+ninja==1.11.1.4
 jupyter-book==1.0.4.post1
 breathe==4.35.0
 sphinx-autodoc-typehints==2.3.0
@@ -5,4 +7,4 @@ sphinx-issues==5.0.0
 sphinx-argparse==0.5.2
 msprime==1.3.3
 sphinx-book-theme
-pandas==2.2.3
\ No newline at end of file
+pandas==2.2.3
diff --git a/python/requirements/CI-tests-pip/requirements.txt b/python/requirements/CI-tests-pip/requirements.txt
index 2e162f68d7..6c711f71d9 100644
--- a/python/requirements/CI-tests-pip/requirements.txt
+++ b/python/requirements/CI-tests-pip/requirements.txt
@@ -1,3 +1,5 @@
+meson==1.8.2
+ninja==1.11.1.4
 lshmm==0.0.8
 pytest==8.3.5
 pytest-cov==6.0.0
@@ -11,4 +13,4 @@ networkx==3.2.1
 msgpack==1.1.0
 newick==1.10.0
 kastore==0.3.3
-jsonschema==4.23.0
\ No newline at end of file
+jsonschema==4.23.0
diff --git a/python/setup.py b/python/setup.py
deleted file mode 100644
index 0f8e77abdb..0000000000
--- a/python/setup.py
+++ /dev/null
@@ -1,45 +0,0 @@
-import os
-import platform
-
-import numpy
-from setuptools import Extension
-from setuptools import setup
-
-IS_WINDOWS = platform.system() == "Windows"
-
-
-libdir = "lib"
-kastore_dir = os.path.join(libdir, "subprojects", "kastore")
-tsk_source_files = [
-    "core.c",
-    "tables.c",
-    "trees.c",
-    "genotypes.c",
-    "stats.c",
-    "convert.c",
-    "haplotype_matching.c",
-]
-sources = (
-    ["_tskitmodule.c"]
-    + [os.path.join(libdir, "tskit", f) for f in tsk_source_files]
-    + [os.path.join(kastore_dir, "kastore.c")]
-)
-
-defines = []
-libraries = []
-if IS_WINDOWS:
-    libraries.append("Advapi32")
-    defines.append(("WIN32", None))
-
-_tskit_module = Extension(
-    "_tskit",
-    sources=sources,
-    extra_compile_args=["-std=c99"],
-    libraries=libraries,
-    define_macros=defines,
-    include_dirs=["lwt_interface", libdir, kastore_dir, numpy.get_include()],
-)
-
-setup(
-    ext_modules=[_tskit_module],
-)
diff --git a/python/subprojects/libtskit b/python/subprojects/libtskit
new file mode 120000
index 0000000000..2fcc51115e
--- /dev/null
+++ b/python/subprojects/libtskit
@@ -0,0 +1 @@
+../../c
\ No newline at end of file
diff --git a/python/tskit/_version.py b/python/tskit/_version.py
old mode 100644
new mode 100755
index 9caefdbdab..1528fe2ed0
--- a/python/tskit/_version.py
+++ b/python/tskit/_version.py
@@ -1,4 +1,8 @@
+#!/usr/bin/env python3
 # Definitive location for the version number.
 # During development, should be x.y.z.devN
 # For beta should be x.y.zbN
 tskit_version = "0.6.5.dev0"
+
+if __name__ == "__main__":
+    print(tskit_version)
diff --git a/python/tskit/meson.build b/python/tskit/meson.build
new file mode 100644
index 0000000000..cb21b34726
--- /dev/null
+++ b/python/tskit/meson.build
@@ -0,0 +1,18 @@
+src = files(
+  'cli.py',
+  'combinatorics.py',
+  'drawing.py',
+  'exceptions.py',
+  'genotypes.py',
+  '__init__.py',
+  'intervals.py',
+  '__main__.py',
+  'metadata.py',
+  'provenance.py',
+  'stats.py',
+  'tables.py',
+  'text_formats.py',
+  'trees.py',
+  'util.py',
+  'vcf.py',
+)