In close collaboration with E.F. Johnson significant progress has been made in the past year toward understanding the structures of mammalian cytochrome P450s, heme containing enzymes essential to the production of naturally occurring metabolites, the degradation of xenobiotic compounds, and the metabolism of a wide variety of small molecule drugs. The crystal structure of the first mammalian P450 enzyme to be determined, rabbit liver 2C5, has been extended to 2.1 Angstrom resolution, and complexes have been solved with the natural substrate progesterone, and two drugs, diclofenac and sulfaphenazole. Recently, diffraction quality crystals of the human enzyme 2C9 have been obtained. These structures are providing key insights into the basis of substrate specificity and mechanism of action of cytochrome P450s. In particular, the structures reveal a remarkable ability of the protein to change conformation in order to bind and recognize these very different compounds. While these crystal structures are being refined, additional complexes are being prepared and solved of the reduced enzyme, of the enzyme in intermediate states of binding, and for other substrates and drugs, in order to understand the relationship between enzyme conformation and activity.