Previous studies have shown that α4β1 (very late activation antigen-4 [VLA-4]) and vascular ceil adhesion molecule-1 (VCAM-1) play a major role in hematopoietic progenitor cell (HPC) homing to bone marrow (BM). However, the antibody used to block VLA-4 function in the mouse (hybridoma clone PS/2) is not specific to VLA-4 but inhibits both α4β1 and α4β7 integrins. Here we have evaluated the contribution of α4β 7 in HPC homing to BM. LineagenegSca-1posc- kitpos cells from adult mouse BM and the factor-dependent cell progenitor (FDCP)-mix progenitor cell line express similar levels of α4β7 by flow cytometry. The α4β7 complex was functional since the chemokine CXCL12 enhanced the adhesion of FDCP-mix to immobilized mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and this was completely abrogated by anti-α4β7 (hybridoma clone DATK32) or anti-α4 integrins (PS/2). BM intravital microscopy revealed that α4β7 plays a predominant role in initial tethering and roiling but not in firm adhesion of FDCP-mix cells. Using homing assays, we demonstrate that α4β7 on HPCs contributes to about half of all α4 integrin-mediated homing activity following BM transplantation. MAdCAM-1 is likely expressed since its inhibition significantly reduced HPC homing. Although there may be other α4β7 integrin ligands involved (eg, fibronectin and VCAM-1), these data thus suggest that α4β7 and its counterreceptor MAdCAM-1 represent a novel adhesion pathway mediating HPC homing to BM.