Pediatric central nervous system tumors are the most common solid tumor of 
childhood. Of these, approximately one-third are gliomas that exhibit diverse 
biological behaviors in the unique context of the developing nervous system. 
Although low-grade gliomas predominate and have favorable outcomes, up to 20% of 
pediatric gliomas are high-grade. These tumors are a major contributor to 
cancer-related morbidity and mortality in infants, children, and adolescents, 
with long-term survival rates of only 10 to 15%. The recent discovery of somatic 
oncogenic mutations affecting chromatin regulation in pediatric high-grade 
glioma has markedly improved our understanding of disease pathogenesis, and 
these findings have stimulated the development of novel therapeutic approaches 
targeting epigenetic regulators for disease treatment. We review the current 
perspective on pediatric high-grade glioma genetics and epigenetics, and discuss 
the emerging and experimental therapeutics targeting the unique molecular 
abnormalities present in these deadly childhood brain tumors.