A recent review (Acevedo O, Jorgensen WL. Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions. Acc Chem Res 2010, 43:142–151) examined our use and development of a combined quantum and molecular mechanical (QM/MM) technique for modeling organic and enzymatic reactions. Advances included the pairwise‐distance‐directed Gaussian (PDDG)/PM3 semiempirical QM (SQM) method, computation of multidimensional potentials of mean force (PMF), incorporation of on‐the‐fly QM in Monte Carlo simulations, and a polynomial quadrature method for rapidly treating proton‐transfer reactions. This article serves as a follow‐up on our progress. Highlights include new reactions, alternative SQM methods, a polarizable OPLS force field, and novel solvent environments, e.g., ‘on water’ and room temperature ionic liquids. The methodology is strikingly accurate across a wide range of condensed‐phase and antibody‐catalyzed reactions including substitution, decarboxylation, elimination, isomerization, and pericyclic classes. Comparisons are made to systems treated with continuum‐based solvents and ab initio or density functional theory (DFT) methods. Overall, the QM/MM methodology provides detailed characterization of reaction paths, proper configurational sampling, several advantages over implicit solvent models, and a reasonable computational cost. WIREs Comput Mol Sci 2014, 4:422–435.This article is categorized under: Electronic Structure Theory > Combined QM/MM Methods