An understanding of the role of human cytochromes (CYPs) P450 in the metabolism of proton pump inhibitors (PPIs) is important in assuring the safety of these drugs. Species' differences in the metabolism of PPIs tend to overestimate the risk of some forms of toxicity in humans. Therefore, information on metabolism by human enzymes is essential for the prediction of drug interactions, or the lack of them. Although extrapolation from population mean data to the individual patient should be made with care, available data indicate that the use of PPIs, omeprazole, lansoprazole and particularly pantoprazole, should be relatively free of clinically-significant drug interactions. This finding may reflect the level of therapeutic dosages for PPIs, and their short elimination half-lives with respect to exposure to drug-metabolizing enzymes. Concern about low-grade induction of CYPIA-mediated procarcinogen metabolism suggests a need for vigilance on the long-term use of PPIs.