Epigenetic silencing of tumor suppressor genes (TSG) is a fundamental incident in the pathogenesis of human cancer. Inactivation of TSG is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. Of the most frequently hypermethylated TSG, Ras Association Domain Family1 (RASSF1A), P16 and Death Association Protein kinase (DAPK) genes. Aberrant hypermethylation of these genes have been correlated with non small cell lung cancer (NSCLC) promoting disease recurrence and remote metastasis. This review aims to provide the readers with a precise description of the research to date in the field of epigenetics and its impact on people with NSCLCs. The focus of this study will be on promoter hypermethylation of three different lung cancer associated genes P16, RASSF1A and DAPK and how these genes inactivated and contribute to the pathogenecity of human malignancies. Moreover, The study aims to investigate the impact of tobacco smoke on the hypermethylation frequency of the mentioned genes. Thus, the promoter hypermethylation frequency could be a promising biomarker to improve NSCLC diagnosis and screening.