The molecular mechanics‐Poisson‐ Boltzmann surface area (MM‐PBSA) and MM‐generalized‐Born surface area (MM‐GBSA) approaches are commonly used in molecular modeling and drug design. Four critical aspects of these approaches are investigated for their effect on calculated binding energies: (1) the atomic partial charge method used to parameterize the ligand force field, (2) the method used to calculate the solvation free energy, (3) inclusion of entropy estimates, and (4) the protonation state of the ligand. As presented on page 2566 by David J. D. Wilson and colleagues, HIV protease is used as a test case with six structurally different inhibitors covering a broad range of binding strength to assess the effect of these four parameters.