Cytochrome P450 monooxygenases provide important pathways for the metabolic clearance of drugs and toxins in humans. These enzymes are expressed from multiple genes and exhibit complex patterns of differential and overlapping substrate selectivity. Recent structures of microsomal P450s determined by X-ray crystallography have provided a structural basis for understanding differences in Substrate recognition. This review will describe similarities and differences in the active site structures Of four human microsomal cytochrome P450 monooxygenases, 2A6, 2C8, 2C9, and 3A4, that contribute extensively to drug and toxin metabolism. (c) 2005 Elsevier Inc. All rights reserved.