The laminin receptor integrin α6 chain is ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells. We have studied its role for homing of stem and progenitor cells to mouse hematopoietic tissues in vivo. A function-blocking anti–integrin α6 antibody significantly reduced progenitor cell homing to bone marrow (BM) of lethally irradiated mice, with a corresponding retention of progenitors in blood. Remarkably, the anti–integrin α6 antibody profoundly inhibited BM homing of long-term multilineage engrafting stem cells, studied by competitive repopulation assay and analysis of donor-derived lymphocytes and myeloid cells in blood 16 weeks after transplantation. A similar profound inhibition of long-term stem cell homing was obtained by using a function-blocking antibody against α4 integrin, studied in parallel. Furthermore, the anti–integrin α6 and α4 antibodies synergistically inhibited homing of short-term repopulating stem cells. Intravenous injection of anti–integrin α6 antibodies, in contrast to antibodies against α4 integrin, did not mobilize progenitors or enhance cytokine-induced mobilization by G-CSF. Our results provide the first evidence for a distinct functional role of integrin α6 receptor during hematopoietic stem and progenitor cell homing and collaboration of α6 integrin with α4 integrin receptors during homing of short-term stem cells.