Genetic polymorphisms in the oxidative metabolism of debrisoquine, mephenytoin, phenformin, sparteine, and tolbutamide have been discovered during recent years. Among these pharmacogenetic conditions, polymorphic oxidation of debrisoquine and sparteine has been intensively studied. Two phenotypes, the extensive (EM) and the poor (PM) metabolizers, have been observed in all populations so far investigated. The PM phenotype exhibits a grossly impaired or nearly absent capacity to metabolize these drugs. The incidence of the PM phenotype in European populations ranges from 5 to 9%. Pronounced variations in the incidence of the PM phenotype have been demonstrated among different ethnic groups. The metabolism of debrisoquine and sparteine is determined by two alleles at a single gene locus; PMs are homozygous for an autosomal recessive gene. Because of markedly impaired metabolism, the PM phenotype develops side effects if normal doses of debrisoquine and sparteine are administered. Defective metabolism in the PM phenotype is not restricted to debrisoquine and sparteine. Impaired metabolism of guanoxan , phenformin, perhexiline, methoxyamphetamine, phenacetin, encainide, metoprolol, alprenolol, bufuralol, nortriptyline, and desipramine have been described. As a consequence of impaired metabolism of these drugs, toxicity and therapeutic failure are observed in the PMs. With regard to molecular mechanisms, studies with microsomes from human liver provide evidence that in the PM phenotype a cytochrome P-450 isozyme is either missing or functionally inadequate.