The release of hematopoietic progenitor cells (HPCs) from bone marrow (BM) is under tight homeostatic control. Under stress conditions, HPCs migrate from BM and egress into circulation to participate in immune response, wound repair, or tissue regeneration. Hemorrhagic shock with resuscitation (HS/R), resulting from severe trauma and major surgery, promotes HPC mobilization from BM, which, in turn, affects post-HS immune responses. In this study, we investigated the mechanism of HS/R regulation of HPC mobilization from BM. Using a mouse HS/R model, we demonstrate that the endogenous alarmin molecule high-mobility group box 1 mediates HS/R-induced granulocyte colony-stimulating factor secretion from macrophages (Mϕ in a RAGE [receptor for advanced glycation end products] signaling-dependent manner. Secreted granulocyte colony-stimulating factor, in turn, induces HPC egress from BM. We also show that activation of β-adrenergic receptors on Mϕ by catecholamine mediates the HS/R-induced release of high-mobility group box 1. These data indicate that HS/R, a global ischemia-reperfusion stimulus, regulates HPC mobilization through a series of interacting pathways that include neuroendocrine and innate immune systems, in which Mϕ play a central role.