In this issue of Blood, Martelli et al and El Hajj et al independently report that nucleophosmin-1 (NPM1)-mutant leukemia is particularly vulnerable to a novel strategy combining all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). The era of targeted therapy has seen some of its greatest successes in the hematologic arena (eg, breakpoint cluster region [BCR]/Abelson [ABL] kinase inhibitors in chronic myeloblastic leukemia and ATRA in acute promyelocytic leukemia [APL]). Moreover, addition of ATO, an agent that induces oxidative stress and interferes with protein translation, to ATRA sharply increases APL cell killing to the extent that cures in this disease are no longer unrealistic. A theoretical (and practical) basis for translating ATRA/ATO-based strategies to non-APL acute myelocytic leukemia (AML) is currently lacking.