SummaryIn this review, after a short discussion of our knowledge about cytochrome P450 isoenzymes, two important sources of variability in the metabolism of drugs by cytochrome P450 are described, i.e. genetic factors and drug-drug interactions. Many hepatic cytochrome P450 enzymes play an important role in the oxidative biotransformation of numerous drugs and other foreign compounds, and of many endogenous substrates. In humans more than 20 different isoenzymes of cytochrome P450 responsible for the hepatic metabolism of drugs, have been identified. They are classified into families and subfamilies on the basis of the degree of amino acid similarity. Cytochrome P450 isoenzymes are regulated by both genetic and environmental factors. Of particular interest is genetic polymorphism in drug oxidation. Two genetic polymorphisms in drug oxidation are well known, the sparteine/debrisoquine (CYP2D6) polymorphism and the mephenytoin oxidation (CYP2C19) polymorphism. As a result of these polymorphisms, two phenotypes exist in the population, poor and extensive metabolizers. Poor metabolizers may be prone to adverse reactions towards drugs with a narrow therapeutic range. In extensive metabolizers clinically significant drug interactions between drugs metabolized by the same isoenzyme can occur.