Diffuse intrinsic pontine glioma (DIPG) is a lethal midline brainstem tumor that most commonly occurs in children and is genetically defined by substitution of methionine for lysine at site 27 of histone 3 (H3K27M) in the majority of cases. This mutation has since been shown to exert an influence on the posttranslational epigenetic landscape of this disease, with the loss of trimethylation at lysine 27 (H3K27me3) the most common alteration. Based on these findings, a number of drugs targeting these epigenetic changes have been proposed, specifically that alter histone trimethylation, acetylation, or phosphorylation. Various mechanisms have been explored, including inhibition of H327 demethylase and methyltransferase to target trimethylation, inhibition of histone deacetylase (HDAC) and bromodomain and extraterminal (BET) to target acetylation, and inhibition of phosphatase-related enzymes to target phosphorylation. This chapter reviews the current rationales and progress made to date in epigenetically targeting DIPG via these mechanisms.