However, as a significant proportion of CDKN2A/CDKN2B alterations are due to gene inactivation by promoter and gene methylation, their gene reactivation by the use of small molecules targeting the epigenetic machinery, including histone and DNA methylases and acetylases, could represent an attractive HNSCC management strategy [70]. The gene discussed is CDKN2B; the disease is head and neck squamous cell carcinoma.