In this issue of Blood, Yan et al and Walz et al exploit mouse genetics to investigate the contribution of signal transducer and activator of transcription 5 (STAT5) to the abnormal in vivo growth of hematopoietic cells expressing JAK2(V617F) or BCR-ABL. Eliminating STAT5 expression had dramatic effects in both contexts, and this new work and other recent studies support the therapeutic potential of targeting pathways regulated by this important signaling molecule in patients with myeloproliferative neoplasms (MPNs).