This Overview describes the general concepts behind the quantum chemical cluster approach for modeling enzyme active sites and reaction mechanisms. First, the underlying density functional electronic structure method is briefly recapitulated. The cluster methodology is then discussed, including the important observation on the convergence of the solvation effects. The concepts are illustrated using examples from recent applications, such as the discrimination between different reaction mechanisms in phosphotriesterase, the elucidation of origins of regioselectivity in the epoxide-opening reaction of haloalcohol dehalogenase, and finally the use of the cluster methodology to establish the detailed structure of the oxygen-evolving complex in photosystem II. © 2011 John Wiley & Sons, Ltd. WIREs Comput Mol Sci 2011 1 323–336 DOI: 10.1002/wcms.13