Oral cancer, a disease associated with major morbidity and mortality, represents a significant worldwide health problem. It is clear that the major etiological factors for oral cancer are tobacco and alcohol exposure. It has been shown that metabolic activation is associated with cancer susceptibility. Various carcinogens and carcinogenic precursors, such as benzopyrene and nitrosamine, have been identified in tobacco smoke, and those are activated or detoxified by two types of metabolic enzymes, phase I and phase II. There are some polymorphisms for these enzyme genes, the functions of which are modified by the types of polymorphisms. On the other hand, there are some genes besides these enzyme genes related to cancer susceptibility. In this review, we discuss the relationships between polymorphisms concerned with oral cancer. Although there are many reports on the polymorphisms related to oral cancer, the results of these reports are controversial. Further studies are needed to evaluate the interactions between carcinogens and the genetic polymorphisms.