Diffusely infiltrating gliomas are inherently heterogeneous tumors, and there 
are ongoing efforts to establish a classification scheme that incorporates new 
molecular and traditional histologic features. In less than a decade, 
high-throughput sequencing of gliomas has transformed the field, uncovering 
several pivotal, highly prevalent genetic alterations that stratify patients 
into different prognostic and treatment-response categories. We highlight the 
genetic aberrations recently discovered in isocitrate dehydrogenase, alpha 
thalassemia/mental retardation syndrome X-linked, death-domain-associated 
protein, histone H3.3, and telomerase reverse transcriptase and discuss how 
these mutations lead to unexpected changes in the epigenetic landscape in 
gliomas. We describe the opportunities these discoveries might provide for the 
development of novel targeted therapy aimed at reversing early epigenetic 
aberrations in glioma precursor cells. Finally, we discuss the challenges for 
effective treatment of this fatal disease posed by intratumoral heterogeneity 
and clonal evolution.