The structure of microsomal P450 2C5 is the first structure of a membrane P450 to be determined by x-ray diffraction. This enzyme was originally identified as a progesterone 21-hydroxylase that is polymorphically expressed in rabbit liver. In contrast to the adrenal 21-hydroxylase, P450 2C5 metabolizes structurally diverse substrates that include a variety of steroids as well as therapeutic drugs. The flexible architecture of the enzyme and the residual solvation of the substrate provide a basis for understanding the catalytic diversity of 2C5 and related drug metabolizing P450s. In addition, the structure of P450 2C5 suggests how mammalian P450s have adapted for membrane binding and interaction with microsomal P450 reductase.