Tobacco use is such a major determinant of head and neck cancer risk that classical epidemiologic techniques were more than adequate to document and characterize the etiologic association. However, the new emphasis in epidemiologic research is multidisciplinary, centering on the role of interindividual differences in susceptibility to carcinogenic exposures and particularly on the interaction of genetic susceptibility and environmental forces, that is, ecogenetics. For upper aerodigestive tract cancers, measurements of carcinogen metabolic activation and DNA repair capability are especially relevant. These susceptibility markers will enable the identification of high-risk population subgroups who can be targeted for the most intensive primary and secondary preventive strategies.