The human cytochrome P450 enzymes and their substrates are reviewed, together with current knowledge on the three-dimensional structures of P450s obtained from X-ray crystallographic studies and from homology modelling based on mammalian P450 template crystal structures. There is a particular focus on human Phase 1 drug metabolism mediated by P450s, and a rationalization of their substrate selectivities and binding strengths in terms of lipophilicity and active site interactions. The combination of molecular modelling and quantitative structure-activity relationship (QSAR) studies facilitates understanding of the factors which determine substrate selectivity and binding to the human drug-metabolizing P450s.