This Overview describes the general concepts behind the quantum chemical clusterapproach formodeling enzyme active sites and reaction mechanisms. First, theunderlying density functional electronic structure method is briefly recapitulated.The cluster methodology is then discussed, including the important observationon the convergence of the solvation effects. The concepts are illustrated usingexamples from recent applications, such as the discrimination between differentreaction mechanisms in phosphotriesterase, the elucidation of origins of regioselectivityin the epoxide-opening reaction of haloalcohol dehalogenase, and finallythe use of the cluster methodology to establish the detailed structure of theoxygen-evolving complex in photosystem II.