In this issue of Blood, Schulze et al use a tetracycline-inducible Dnmt3b knock-in mouse model to investigate how DNMT3B-mediated DNA methylation affects leukemogenesis. Increased DNMT3B expression prolonged survival in retrovirally induced Myc-Bcl2– or MLL-AF9–driven leukemia, and acute myeloid leukemia (AML) patients with high expression of DNMT3B target genes showed inferior overall survival.