CDKN2A gene functions as an important tumor suppressor via induction of cell growth arrest and senescence. Majority of the CDKN2A mutations result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Somatic mutations of CDKN2A are present in various tumor types including ~2-3% of hepatocellular carcinoma (HCC). However, epigenetic silencing of CDKN2A by promoter hypermethylation is more frequent, occurring in 73% of HCC, 56% of HBV-related HCC, and 84% of HCV-related HCC. Clinical trials for CDKN2A deficient tumors are available. Correlation with other clinical and lab findings is necessary.