Activation of the serine-threonine kinase AKT is associated with tumor promotion, whereas its downstream FOXO transcription factor targets are associated with tumor-suppressor functions. Now, David Scadden and colleagues show that AKT and FOXOs have opposite roles from the expected in acute myeloid leukemia (AML) (Cell 146, 697–708, 2011). The authors used a mouse model in which AML is induced with a MLL-AF9 fusion protein and showed that leukemic progenitor cells have diminished Akt activity and enhanced FoxO activity compared to normal myeloid progenitor cells. Constitutive activation of Akt or deletion of Foxo1, Foxo3 and Foxo4 in cultured cells increased expression of markers of myeloid differentiation. In vivo Cre-mediated knockout of Foxo1, Foxo3 and Foxo4 delayed the onset of leukemia and impaired leukemia-initiating cell function. The authors also showed that human AML cell lines with the MLL-AF9 translocation have active FOXO3, and knockdown of FOXO3 increased expression of markers of myeloid maturation and apoptosis and activated the JNK–c-JUN signaling pathway that is involved in myeloid differentiation. Pharmacological inhibition of JNK acted synergistically with knockdown of FOXO3 to increase expression of markers of myeloid maturation and apoptosis. This work suggests that the AKT-FOXO and JNK–c-JUN signaling pathways may be useful therapeutic targets to treat AML.