According to GLOBOCAN 2008, there were 12.7 million new cancer cases and 7.6 million deaths. Among these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Oral cancer accounted for 3-4% of all cancers. There were 263,900 oral cancer cases, with almost two-thirds of them occurring in men. Oral cancer is among the leading cancer types in south central Asian men. In India, oral cancer is the leading cancer type among men and third most common cancer among women [1]. There have also been impressive advances in recent years regarding the detection, prevention, and treatment of OSCC. Unfortunately, however, the overall 5-year survival for OSCC continues to be modest at its best. OSCC survival is highly dependent on the stage of the tumour at diagnosis. For example, Stage I cancers have an 80% 5-year survival rate, while the survival rate decreases to 20% for Stage IV lesions [2]. To improve long-term outcomes, an early detection, in conjunction with primary and secondary prevention strategies, is critical. Screening and an early detection are believed to decrease both the morbidity and mortality which are associated with OSCC, because unlike many anatomic sites, in the oral cavity, pre-malignant lesions are often visible on clinical examination. However, an accurate discrimination between premalignant vs reactive/inflammatory lesions via conventional visual and tactile examinations alone is problematic. As the malignant potential of oral lesions cannot be accurately predicted solely on the basis of their clinical characteristics, a histological evaluation is essential for all suspicious lesions. The definition of an oral mucosal pre-malignancy that is based on a conventional histologic examination can also be problematic. Lesions are currently considered as pre-cancerous when there are cytomorphologic changes which are consistent with dysplasia. However, the various criteria for diagnosing and grading dysplasia are controversial, highly subjective and open to a wide range of interpretation, even among highly qualified pathologists [3,4]. In addition, no definitive criteria currently exist for predicting the risk of a cancerous transformation of individual dysplastic lesions; even dysplastic oral lesions have been reported to undergo spontaneous regression. Therefore, conventional histologic findings can only be utilized to indicate that a given lesion may have a malignant potential, and that it cannot be used for the prediction of a malignant change. Hence, two key issues should be considered: In general, a progression to OSCC may not occur in a linear fashion over a uniform period of time. Rather, there are subsets of lesions with histologic evidences of dysplasia, that may or may not progress to OSCC. Similarly, the histologically normal’ appearing mucosal lesions may truly be benign or they may represent molecular premalignant lesions that have not yet developed morphologic / cytologic changes which are consistent with dysplasia [5]. Current modeling postulates that the development of cancer is driven by the accumulation of genetic and epigenetic changes within a clonal population of cells. These genotypic alterations can affect hundreds of genes, leading to phenotypic changes in critical cellular functions, such as resistance to cell death, increased proliferation, induction of angiogenesis, and the ability to invade and metastasize. The mechanisms which underlie these genetic and epigenetic aberrations include, but are not limited to, genomic instability through chromosomal rearrangements, amplifications, deletions, methylations and mutations. This article gives a brief review on various genetic and epigenetic alterations which are observed in the potentially malignant lesions that are likely to progress to cancer.