The transcription factor cAMP response-element binding protein (CREB) participates in a diverse array of cellular processes, including survival, proliferation and glucose metabolism. A new report by Shankar et al. shows that patients with acute myeloid leukemia (AML) have a greater incidence of relapse when intracellular levels of CREB are elevated. By enhancing expression of certain cell-cycle genes, CREB appears to promote growth-factor-independent proliferation and survival of myeloid cells. The results provide new insights into CREB function and suggest potential avenues for therapeutic intervention.