In this issue of Blood, Mar et al describe the effect of inactivating mutations of the histone methyltransferase (HMT) SETD2 in accelerating leukemia pathogenesis and conferring therapy resistance. Mutations of epigenetic regulators are among the commonest lesions in malignancy. These include mutations of HMTs that modify histone tails protruding from the nucleosome. For example, inactivation of EZH2, responsible for histone H3 lysine 27 trimethylation (H3K27me3), a modification associated with gene silencing, occurs in myelodysplasia and acute myeloid leukemia (AML), whereas mutation of KMT2D, responsible for the H3K4me1 modification found at enhancers, is common in lymphoma. These enzymes change the chemical composition of chromatin at gene regulatory sites, affecting transcriptional initiation. By contrast, SETD2 has a role downstream of the transcriptional start site (TSS).