In parts of the developing world (South Central Asia in particular), squamous cell carcinoma of the head and neck (SCCHN) is one of the most common malignancies encountered. Although tobacco and alcohol are clearly defined as etiologic factors in these malignancies, clinical observations have suggested that inherited genetic factors put some individuals at increased risk for SCCHN. Emerging data (both phenotypic and genotypic) support this concept of genetic susceptibility to SCCHN and point to differences in DNA repair ability, carcinogen metabolism, and cell cycle control as the systems important to the risk of tobacco-induced malignancies. The ability to identify such high-risk individuals will have major influences on the practice of cancer prevention in the future.