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Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-XL, and Mcl-1) or agonists (e.g., Bax, Bad, and Bak). Here we report that among the Bcl-2 family of proteins tested (Bcl-2, Bcl-XL, Mcl-1, Bax, Bad, and Bak), Bcl-XLwas unique in that its protein levels were tightly regulated by hemopoietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that the regulation of Bcl-XLprotein levels is mediated by the Jak kinase pathway and is independent of other signaling effectors including STATs, PI-3′ kinase, and Ras. Moreover, we provide the first direct evidence thatBcl-Xis altered in cancer, becausebcl-Xexpression was activated selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboringbcl-Xinsertions had alteredbcl-XRNAs, expressed elevated levels of Bcl-XLprotein, and lacked the requirements for cytokines normally essential for cell survival. Finally, overexpression of Bcl-XLeffectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Therefore, Bcl-XLfunctions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.