Wide variability in response to some drugs such as debrisoquine can be attributed largely to genetic polymorphism of their oxidative metabolism. Most beta-blockers undergo extensive oxidation. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers (PMs) of debrisoquine have claimed that the oxidation of these drugs is under polymorphic control. Subsequently, controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol, timolol and bopindolol. The poor metaboliser phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, viz. alpha-hydroxylation and O-demethylation of metoprolol and 1'- and possibly 4- and 6-hydroxylation of bufuralol. In contrast, the overall pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lower in poor metabolisers. As anticipated, the disposition of atenolol which is eliminated predominantly unchanged by the kidney and in the faeces, is unrelated to debrisoquine phenotype. The clinical significance of impaired elimination of beta-blockers is not clear. If standard doses of beta-blockers are used in poor metabolisers, these subjects may be susceptible to concentration-related adverse reactions and they may also require less frequent dosing for control of angina pectoris.