There are measurable differences, genetically determined, in susceptibility to carcinogenic activity. Variation in metabolism of xenobiotic chemicals is one determinant of susceptibility and is attributed to polymorphisms in a number of enzymes. There may also be a wide spectrum of DNA-repair capability within the population. A peripheral lymphocyte assay has been developed in which in vitro bleomycin-induced chromosome breaks provides an indirect measurement of such repair. Mutagen sensitivity as defined by this assay has been shown to be an independent risk factor for tobacco-related malignancies, especially those of the upper aerodigestive tract. Preliminary data also suggest familial aggregation of cancer in mutagen-sensitive patients. Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. These susceptibility markers will enable us to identify high-risk population subgroups that can be targeted for intensive primary and secondary preventive strategies.