Brain tumors are the most common solid tumors in children. Pediatric high-grade 
glioma (HGG) accounts for ∼8-12 % of these brain tumors and is a devastating 
disease as 70-90 % of patients die within 2 years of diagnosis. The failure to 
advance therapy for these children over the last 30 years is largely due to 
limited knowledge of the molecular basis for these tumors and a lack of disease 
models. Recently, sequencing of tumor cells revealed that histone H3 is 
frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic 
pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying 
either K27M or G34R/V mutations. Although mutations in many chromatin modifiers 
have been identified in cancer, this was the first demonstration that histone 
mutations may be drivers of disease. Subsequent studies have identified 
high-frequency mutation of histone H3 to K36M in chondroblastomas and to G34W/L 
in giant cell tumors of bone, which are diseases of adolescents and young 
adults. Interestingly, the G34 mutations, the K36M mutations, and the majority 
of K27M mutations occur in genes encoding the replacement histone H3.3. Here, we 
review the peculiar characteristics of histone H3.3 and use this information as 
a backdrop to highlight current thinking about how the identified mutations may 
contribute to disease development.