CDKN2A gene encodes p16 and functions as an important tumor suppressor in various human malignancies. Its activation prevents carcinogenesis via induction of cell growth arrest and senescence. The 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. CDKN2A alterations are common, occurring in 60-70% of gallbladder carcinomas, by mechanisms including point mutations, chromosomal loss, and promoter methylation. These somatic CDKN2A alterations are associated with a poor prognosis. A frameshift insertion at codon 57 in exon 2 will result in early truncation of the p16 protein. Multiple clinical trials are available for patients with CDKN2A deficient tumors.