Recent studies have shown that chromatin-associated proteins and transcription factors have more somatic alterations than any other class of oncoproteins in childhood CNS tumors. Different H3 genes/variants can be affected with remarkable specific association between tumor location/type and the particular H3 residue or variant that is mutated. This observation, along with the high prevalence of H3 mutations in pediatric and young adult HGA and bone tumors, suggest that these oncohistones are selected for in the context of organ development. These ground-breaking discoveries of oncohistones implicate a direct effect of epigenetic misregulation in oncogenesis, and what we know of their effects along with novel tools needed to study them will be described in this symposium. We will also describe how we are harnessing synergies between cancer genomics approach and chemical biology approaches to help make sense of the pathogenesis of oncohistones.