Cytochrome P450 (P450) enzymes play dominant roles in the metabolism of toxic chemicals, as well as drugs, steroids, and several other important groups of compounds. The human genome contains 57 P450 ( CYP) genes, about one-fourth of which can play potential roles in xenobiotic biotransformation. The P450s in experimental animal models are similar but not identical to the human P450s, in the context of gene organization, primary sequences, regulation, and catalytic activities. The major mechanism of P450 regulation is transcriptional control by heterodimeric receptors. The crystal structures of several important human P450s have now been determined, revealing similar folds, variability of certain regions giving rise to a 5-fold range in size of the active site, and plasticity that allows at least some ligands to bind with elements of an induced-fit process. The chemistry of P450 reactions is understood in the context of high-valent iron–oxygen chemistry and involves abstraction of hydrogen atoms or non-bonded electrons. Rate-limiting steps in catalysis vary with individual P450s and substrates. P450s play important roles in modulating the toxicity of chemicals, either detoxicating dangerous materials or activating non-toxic compounds to reactive forms. For instance, elimination of P450 2e1 (and 1a2) in mice greatly attenuates the in vivo toxicity of acetaminophen. P450s have also been implicated in several toxic drug–drug interactions in humans. Another area of toxicity in which P450s are important is chemical carcinogenesis, with good evidence for P450 contribution in animal models.