Somatic mutations of CDKN2A are present in various tumor types, including, squamous cell carcinoma of the larynx, clear cell sarcoma, head and neck cancer, esophageal cancer and melanoma. Germline aberrations in the CDKN2A gene are also observed in some melanoma-prone families, representing high penetrance mutations. Majority of the CDKN2A mutations span exon 2 and result in loss or decreased binding to CDK4/6 leading to uncontrolled cell growth through inactivation of Rb and p53 pathways. Multiple preclinical and clinical studies are ongoing for CDKN2A deficient tumors in multiple tumor types. Correlation with clinical findings and genetic counseling may be helpful if there is clinical concern for an inherited cancer syndrome.