The activating IDH2^R140Q mutation promotes accumulation of the oncometabolite(R)-2-hydroxyglutarate (2HG) to drive acute myeloid leukemia (AML) in a subset of patients. Yen and colleagues generated a potent allosteric inhibitor of IDH2^R140Q, AG-221, which reduced 2HG production, promoted differentiation of AML blasts, and extended survival in AML xenografts. In a related study, Shih, Meydan, and colleagues showed that AG-221 reversed aberrant DNA hypermethylation and induced differentiation in IDH2^R140Q AML cells, and the DNA hypomethylating agent 5-Azacytidine had similar effects in TET2-mutant AML. Both AG-221 and 5-Azacytidine cooperated with a FLT3 inhibitor to reverse aberrant hypermethylation and suppress leukemic stem cells. Together, these studies indicate that DNA hypomethylating agents can promote AML differentiation and may cooperate with other inhibitors. For details, please see the article by Yen and colleagues on page 478 and the article by Shih, Meydan, and colleagues on page 494.