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. CDKN2A alterations have been reported as frequent mutations in squamous cell carcinomas of different primary sites including the lung, head and neck, and skin. CDKN2A R80* results in a premature truncation and confers a loss of function to the CDKN2A protein as demonstrated by loss of CDK binding. CDKN2A truncating mutations, including R80*, have been described in approximately 4% of esophageal squamous cell carcinomas. CDKN2A/CDKN2B loss may be associated with increased sensitivity to CDK4/6 inhibitors. The efficacy and toxicity profiles of these inhibitors in the context of a variety of cancer types are currently under evaluation in clinical trials. The clinical significance of the loss of one copy of CDKN2A remains to be fully elucidated in squamous cell carcinoma of the esophagus. These results should be interpreted in the clinicopathologic context.