Hematopoiesis can be scripted into multiple acts that open with hematopoietic stem cells (HSCs) and close with the production of nonproliferating mature blood cells. Its lifelong durability requires that HSCs choose between mutually exclusive fates: self-renewal versus a capacity for multilineage differentiation. The growth factor independence 1 (Gfi-1) oncoprotein was first discovered playing supporting roles in lymphopoiesis and myelopoiesis. Two new studies indicate that Gfi-1 regulates self-renewal and preserves the functional integrity of HSCs, adding Gfi-1 to the short list of intrinsic regulators of self-renewal and casting it among the major players featured in starring roles in hematopoiesis.