diff --git a/.flake8 b/.flake8
index 7b93065c4..0b75922b4 100644
--- a/.flake8
+++ b/.flake8
@@ -16,6 +16,5 @@ exclude =
   .venv,
   __init__.py,
   docs,
-  setup.py
   external
   operator_estimation.py
diff --git a/.gitlab-ci.yml b/.gitlab-ci.yml
index 127093558..5f875e604 100644
--- a/.gitlab-ci.yml
+++ b/.gitlab-ci.yml
@@ -14,9 +14,6 @@ cache:
     - .cache/pip
     - .venv
 
-.install-dephell: &install-dephell # Install dephell to auto-generate setup.py
-  - curl -L https://raw.githubusercontent.com/rigetti/dephell/master/install.py | python
-
 .install-npm: &install-npm
   - curl -sL https://deb.nodesource.com/setup_12.x | bash -
   - apt-get update
@@ -166,13 +163,11 @@ PyPI Publish Branch (TestPyPI):
   allow_failure: true
   script:
     - . scripts/ci_install_deps
-    - *install-dephell
     - *install-npm
     - npx semantic-release --branches $CI_COMMIT_BRANCH --dry-run
     - export MOST_RECENT_VERSION=$(git describe --abbrev=0 --tags | sed 's/v//')
     - export VERSION_TAG="${MOST_RECENT_VERSION}.dev${CI_JOB_ID}"
     - poetry version "$VERSION_TAG"
-    - dephell deps convert
     - *publish-pypi-test
   rules:
     # Skip this job if running on master or rc
@@ -188,7 +183,6 @@ PyPI Publish Branch (TestPyPI):
   stage: deploy
   script:
     - . scripts/ci_install_deps
-    - *install-dephell
     - *install-npm
     # This performs the semantic-release configured in package.json.
     # Depending on the config, this may add a tag and then publish a GitLab/GitHub release.
diff --git a/CHANGELOG.md b/CHANGELOG.md
index caaff410e..081576f34 100644
--- a/CHANGELOG.md
+++ b/CHANGELOG.md
@@ -6,6 +6,8 @@ Changelog
 
 ### Announcements
 
+- `setup.py` has been removed and will no longer be generated as part of the automated release process.
+
 ### Improvements and Changes
 
 - Function `pyquil.quilatom.substitute()` now supports substitution of classical `MemoryReference`
diff --git a/package.json b/package.json
index 8bf7437d9..36b4f5167 100644
--- a/package.json
+++ b/package.json
@@ -30,7 +30,7 @@
       }],
       "@semantic-release/github",
       ["@semantic-release/git", {
-        "assets": ["pyproject.toml", "setup.py"],
+        "assets": ["pyproject.toml"],
         "message": "Release v${nextRelease.version} [skip ci]"
       }]
     ],
diff --git a/prepare_release.sh b/prepare_release.sh
index dd8e418f7..36ad39bb4 100755
--- a/prepare_release.sh
+++ b/prepare_release.sh
@@ -1,3 +1 @@
 poetry version $1
-dephell deps convert
-poetry run black setup.py
diff --git a/pyproject.toml b/pyproject.toml
index 403484362..95840e6ea 100644
--- a/pyproject.toml
+++ b/pyproject.toml
@@ -82,10 +82,6 @@ exclude = '''
 )
 '''
 
-[tool.dephell.main]
-from = { format = "poetry", path = "pyproject.toml" }
-to = { format = "setuppy", path = "setup.py" }
-
 [build-system]
 requires = ["poetry-core>=1.0.0"]
 build-backend = "poetry.core.masonry.api"
diff --git a/setup.py b/setup.py
deleted file mode 100644
index 680be2ef1..000000000
--- a/setup.py
+++ /dev/null
@@ -1,91 +0,0 @@
-# -*- coding: utf-8 -*-
-
-# DO NOT EDIT THIS FILE!
-# This file has been autogenerated by dephell <3
-# https://github.com/dephell/dephell
-
-try:
-    from setuptools import setup
-except ImportError:
-    from distutils.core import setup
-
-import os.path
-
-readme = ""
-here = os.path.abspath(os.path.dirname(__file__))
-readme_path = os.path.join(here, "README.rst")
-if os.path.exists(readme_path):
-    with open(readme_path, "rb") as stream:
-        readme = stream.read().decode("utf8")
-
-setup(
-    long_description=readme,
-    name="pyquil",
-    version="3.1.0-rc.4",
-    description="A Python library for creating Quantum Instruction Language (Quil) programs.",
-    python_requires="==3.*,>=3.7.0",
-    project_urls={
-        "documentation": "https://pyquil-docs.rigetti.com",
-        "repository": "https://github.com/rigetti/pyquil.git",
-    },
-    author="Rigetti Computing",
-    author_email="softapps@rigetti.com",
-    license="Apache-2.0",
-    keywords="quantum quil programming hybrid",
-    classifiers=[
-        "Development Status :: 5 - Production/Stable",
-        "License :: OSI Approved :: Apache Software License",
-        "Programming Language :: Python :: 3.7",
-        "Programming Language :: Python :: 3.8",
-        "Programming Language :: Python :: 3.9",
-        "Operating System :: OS Independent",
-    ],
-    packages=[
-        "pyquil",
-        "pyquil._parser",
-        "pyquil.api",
-        "pyquil.compatibility",
-        "pyquil.compatibility.v2",
-        "pyquil.compatibility.v2.api",
-        "pyquil.experiment",
-        "pyquil.external",
-        "pyquil.latex",
-        "pyquil.quantum_processor",
-        "pyquil.quantum_processor.transformers",
-        "pyquil.simulation",
-    ],
-    package_dir={"": "."},
-    package_data={"pyquil": ["*.typed"], "pyquil._parser": ["*.lark", "*.md"], "pyquil.external": ["*.md"]},
-    install_requires=[
-        'importlib-metadata==3.*,>=3.7.3; python_version < "3.8"',
-        "lark==0.*,>=0.11.1",
-        "networkx==2.*,>=2.5.0",
-        "numpy==1.*,>=1.20.0",
-        "qcs-api-client<0.13.0,>=0.8.1",
-        "retry==0.*,>=0.9.2",
-        "rpcq==3.*,>=3.6.0",
-        "scipy==1.*,>=1.6.1",
-    ],
-    extras_require={
-        "dev": [
-            "black==20.*,>=20.8.0.b1",
-            "flake8==3.*,>=3.8.1",
-            "mypy==0.740",
-            "pytest==6.*,>=6.2.2",
-            "pytest-cov==2.*,>=2.11.1",
-            "pytest-freezegun==0.*,>=0.4.2",
-            "pytest-mock==3.*,>=3.6.1",
-            "pytest-rerunfailures==9.*,>=9.1.1",
-            "pytest-timeout==1.*,>=1.4.2",
-            "pytest-xdist==2.*,>=2.2.1",
-            "respx==0.*,>=0.15.0",
-        ],
-        "docs": [
-            "nbsphinx==0.*,>=0.8.6",
-            "recommonmark==0.*,>=0.7.1",
-            "sphinx==4.*,>=4.0.2",
-            "sphinx-rtd-theme==0.*,>=0.5.2",
-        ],
-        "latex": ["ipython==7.*,>=7.21.0"],
-    },
-)