Oral squamous cell carcinomas (OSCC) are the most common malignancy of the oral cavity and their multistep development requires the accumulation of multiple genetic and epigenetic alterations. Inactivation of p16^INK4a, encoded by the CDKN2 gene has been widely associated with this type of tumors. The purpose of this review is to elucidate the relationship between p16^INK4a expression and the different clinical and pathological aspects of OSCC, analyze the variation in results between studies, detailing the described genetic/epigenetic alterations that result in gene silencing and the relationship between p16^INK4a and HPV infection.