Chronic alcohol and tobacco abuse plays a crucial role in the development of different liver associateddisorders. Intake promotes the generation of reactive oxygen species within hepatic cells exposing their DNAto continuous oxidative stress which finally leads to DNA damage. However in response to such damage anentangled protective repair machinery comprising different repair proteins like ATM, ATR, H2AX, MRN complexbecomes activated. Under abnormal conditions the excessive reactive oxygen species generation results in geneticpredisposition of various genes (as ADH, ALDH, CYP2E1, GSTT1, GSTP1 and GSTM1) involved in xenobioticmetabolic pathways, associated with susceptibility to different liver related diseases such as fibrosis, cirrhosis andhepatocellular carcinoma. There is increasing evidence that the inflammatory process is inherently associatedwith many different cancer types, including hepatocellular carcinomas. The generated reactive oxygen speciescan also activate or repress epigenetic elements such as chromatin remodeling, non-coding RNAs (micro-RNAs),DNA (de) methylation and histone modification that affect gene expression, hence leading to various disorders.The present review provides comprehensive knowledge of different molecular mechanisms involved in genepolymorphism and their possible association with alcohol and tobacco consumption. The article also showcasesthe necessity of identifying novel diagnostic biomarkers for early cancer risk assessment among alcohol andtobacco users.