Oral squamous cell carcinoma (OSCC) is one of the most common oral cancers accounting for 96% of all head and neck cancers. Beside the different endogenous and environmental risk factors, epigenetics play an important role in causing OSCC. Epigenetics shed light on the presence of inherited changes in the phenotype of a gene with the absence of an alteration in the DNA sequence. The epigenetic modifications can result in the emersion of cancer, autoimmune diseases, aging and other diseases. Under several circumstances, DNA undergoes methylation. This methylation might be related to normal development or serious diseases like cancer. DNA methylation is a heritable biochemical modification occurs predominantly by transferal of a methyl group to C- 5 position of the cytosine ring (CpGs) which may cause epigenetic disturbances. This review aims toward investigating the genetics in literature to help in diagnosing OSCC with new modalities that are less invasive compared to histopathology. Studied genes including ECAD, DAPK, MGMT and P53 has different methylation frequencies in relation to OSCC which may be related to their significant role in early diagnosis and prognosis. Since genetics has a major role in OSCC, we searched most recently reported genes and technologies seeking early detection and treatment of OSCC results in a better prognosis and more conservative treatment.