Potent inhibitors have been reported for both SET domain (EZH2, EHMT1/2, SMYD2, SMYD3, SUV420H1/2, SETD7) and Class I (DOT1L, PRMT5, PRMT1/8, PRMT3, PRMT4, PRMT6) enzymes [1,7], but some PMTs with strong disease association remain so far without high-quality drug-like ligands: recurrent chromosomal aberrations affecting the H3K36 methyltransferase NSD2 lead to oncogenic hyper-trimethylation of H3K36 in myeloma and leukemia [8,9], while amplification of the H3K9 methyltransferase SETDB1 is a driving factor in lung tumorigenesis and melanoma [10,11]. The gene discussed is DOT1L; the disease is leukemia.