Abstract:  The chemokine stromal cell‐derived factor‐1 (SDF‐1/CXCL12) and its receptor, CXCR4, are involved in a number of facets of the regulation of hematopoiesis at the level of hematopoietic stem (HSCs) and progenitor (HPCs) cells. Modulation of this ligand–receptor interaction may be of clinical utility. We now report that: (1) the CC chemokine, macrophage inflammatory protein‐1α (MIP‐1α/CCL3) synergizes with AMD3100 (an antagonist of the binding of SDF‐1/CXCL12 to CXCR4) to rapidly mobilize HPCs to the blood of mice; moreover, the combination of granulocyte colony‐stimulating factor (G‐CSF) with AMD3100 and MIP‐1α/CCL3, given in a specific sequence, mobilizes the greatest number of HPCs compared to any combination of two of these mobilizing agents; (2) pretreatment of recipient mice with Diprotin A, an inhibitor of CD26/Dipeptidylpeptidase IV (DPPIV), enhances the competitive HSCs repopulating capacity of untreated donor cells; (3) the survival‐enhancing effects of SDF‐1/CXCL12 on HPCs subjected in vitro to delayed addition of growth factors (GFs) are mediated in part through the cell cycle‐related proteins p21cip1/waf1 (as assessed using p21cip1/waf1−/− and +/+ mice) and Mad2 (using Mad2 +/− and +/+ mice); and (4) deletion of CD26/DPPIV on mouse bone marrow cells increases the survival‐enhancing effects of SDF‐1/CXCL12 on HPCs. These results demonstrate the means to increase the mobilization of HPCs, the engrafting capability of HSCs, and responsiveness of HPCs to the survival‐enhancing activity of SDF‐1/CXCL12, effects that may be of practical value.