Cytochrome P450 (CYP) family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of structurally and chemically diverse drugs and non-drug xenobiotics. The individual CYP enzymes exhibit distinct substrate and inhibitor selectivities, and hence differing patterns of inhibitory drug–drug interactions. In addition, CYP enzymes differ in terms of regulation of expression, genetic polymorphism, and environmental factors that alter activity. The availability of three-dimensional structures from X-ray crystallography have been invaluable for understanding the structural basis of the ligand selectivity of CYP enzymes. Moreover, the X-ray crystal structures demonstrate that CYP proteins exhibit marked flexibility, particularly around the active site, and the principle of ligand-induced conformational changes is now well accepted. Recent studies have demonstrated that molecular dynamics simulations (MDS) provide an additional approach for modeling the structural flexibility of CYP enzymes, both in the presence and absence of bound ligand, and understanding the functional consequences of plasticity. However, most of the MDS studies reported to date have utilized short simulation time scales, and few have validated the computationally-generated data experimentally (e.g. by site-directed mutagenesis and enzyme kinetic approaches). Although modeling approaches require further development and validation, MDS has the potential to provide a deeper understanding of CYP structure–function than is available from experimental techniques such as X-ray crystallography alone.