PyMOL uses OpenGL Extension Wrangler Library (GLEW) and FreeGLUT, and can solve Poisson–Boltzmann equations using the Adaptive Poisson Boltzmann Solver.

[4] PyMOL used Tk for the GUI widgets and had native Aqua binaries for macOS through Schrödinger, which were replaced with a PyQt user interface on all platforms with the release of version 2.0.

On 1 August 2006, DeLano Scientific adopted a controlled-access download system for precompiled PyMOL builds (including betas) distributed by the company.

In 2017, Schrödinger revamped the distribution system to unify the user interface under Qt and the package management under Anaconda, and released it as PyMol v2.

[5] This version restricts some new functionalities and adds a watermark to the visualization if used unlicensed beyond the 30-day trial period; the overall license policy is similar to the DeLano system.