Studies of most drugs of abuse utilize in vivo animal experimentation so that the responses measured reflect the pharmacokinetics of the administered drug as well as its pharmacodynamics. These drugs are generally lipid soluble chemicals and their elimination is dependent on metabolism, so an understanding of this process is critical to the interpretation of responses. This review summarizes the interaction between drugs of abuse and cytochromes P450, the oxidative enzymes that catalyze the first step of the metabolic process. Although they process their substrates by a common chemical mechanism, these enzymes differ markedly in their regulation, i.e. induction and inhibition, their substrate selectivities, the metabolites they generate and their relative concentration in different species. The activity of an enzyme catalyzing a specific metabolic reaction can be altered by prior xenobiotic exposure, by its genetics and by a co-administered drug, so that the pharmacokinetics of the drug under study can vary with the history of the individual subject. These issues are obviously important in human studies so, when possible, the relevant human enzymes involved in the processes described have been identified.