Previous studies have shown that α₄β₁ (very late activation antigen-4 [VLA-4]) and vascular cell 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 α₄β₇ in HPC homing to BM. Lineage^negSca-1^posc-kit^pos 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 rolling 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.