Abstract: Oral cancer is the sixth most common cancer in the world and most common neoplasm in the India. The exposure to environmental agents and byproducts of cellular metabolism results in damage of DNA, which if left unrepaired, could lead to the process of carcinogenesis. Individual specific difference in the susceptibility to chemical carcinogens is one of the most important factors in the estimate of risk of cancers along with an ability to repair DNA damage. Molecular epidemiological studies have shown that an individual’s susceptibility to oral cancer is modulated by both genetic and environmental factors. Therefore, genetic polymorphisms of phase-1 and phase-2 xenobiotic metabolizing enzymes as well as DNA repair genes can modify an individual’s response to carcinogens and hence, the carcinogenic potential of such exposures. In the present study, we have reviewed the literature about association of polymorphisms of phase 1 enzymes (CYPs), phase 2 enzymes (GSTM1, GSTP1, GSTM3) and DNA repair genes (XRCC1, XRCC3, XPC, HOGG1) with risk of oral cancer, with special emphasis on Indian studies. It can be concluded that the effect of these polymorphisms on oral cancer risk was inconclusive and showed variation in different populations and even within same population. Thus future studies should involve more number of patients as well as more SNP’s of specific gene for better evaluation of significance of genetic markers in oral cancer assessment.