Hematopoietic stem cells facilitate lifelong production of a diverse repertoire of functional mature blood cells. They are a critical biological reservoir that enable organisms to endure physiological challenges such as inflammation, disease, and age. The functional maintenance of hematopoietic stem cells depends not only on intrinsic cell pathways, but also on extrinsic cues that guide core behaviors like homing and self-renewal. Careful study of these extrinsic regulatory networks can deepen our appreciation of fundamental stem cell biology and motivate therapeutic approaches to treat hematologic disease. Here I show how derangement of the bone marrow regulatory environment perturbs normal hematopoiesis, and demonstrate the dependence of hematopoietic stem cells on a circulating endocrine factor.