Genetic polymorphisms of drug-metabolizing enzymes, principally CYP2D6 (debrisoquine 4-hydroxylase), have long been considered influential on host responsiveness to environmental carcinogens. In several independent studies, lung cancer cases are more frequently associated with the extensive metabolizer phenotype of CYP2D6. However, assignment of phenotype has traditionally involved administration of debrisoquine and analysis of drug and metabolite concentrations in patient urine and is thus potentially confounded by concomitant drug therapy and the presence of the tumor itself. The development of molecular genotyping methods offers unique opportunities to obviate these problems and to ascertain the relationship between the presence of individual alleles and disease risk. Preliminary data are presented that indicate that the CYP2D6 wild-type allele may be a predisposing factor in lung cancer.