Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of upper aerodigestive tract cancer. It has been suggested that such polymorphisms may be linked to cancer susceptibility. Using a case-control molecular epidemiologic approach, the association between many of these genetic polymorphisms and susceptibility to upper aerodigestive tract cancer has been investigated in numerous studies. In this review, we summarize the findings of these studies, analyzing potential associations with upper aerodigestive tract cancer risk in terms of gene:environment interactions, genotype-induced functional defects in enzyme activity and/or expression, and the influence of race on these associations.