Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. I will present our efforts in understanding the role of H3K36M in HNSCC, the H3K36M interactome, as well as changes in the epigenome and defects on genome instability mediated by loss of H3K36 methylation. In support of our in vitro findings, I will discuss how PARP1/2 inhibitors alone alone or in combination with agents that upregulate H3K27me3 proves to be successful in reducing HNSCC tumor burden. Our findings underscore a delicate balance between H3K36 and H3K27 methylation, essential for maintaining genome stability in HNSCC. This equilibrium presents promising therapeutic opportunities for patients with H3K36me-deficient tumors.