Under normal conditions, the great majority of hematopoietic stem/progenitors cells (HSPCs) reside in the bone marrow. The number of HSPCs in the circulation can be markedly increased in response to a number of stimuli, including hematopoietic growth factors, myeloablative agents and environmental stresses such as infection. The ability to ‘mobilize’HSPCs from the bone marrow to the blood has been exploited clinically to obtain HSPCs for stem cell transplantation and, more recently, to stimulate therapeutic angiogenesis at sites of tissue ischemia. Moreover, there is recent interest in the use of mobilizing agents to sensitize leukemia and other hematopoietic malignancies to cytotoxic agents. Key to optimizing clinical mobilizing regimens is an understanding of the fundamental mechanisms of HSPC mobilization. In this review, we discuss recent advances in our understanding of the mechanisms by which granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing agent, induces HSPC mobilization.