Purpose of review Hematopoietic stem cell (HSC) transplantation is the most powerful treatment modality for a variety of hematological disorders. Successful hematopoietic recovery after transplantation depends on optimal homing of HSCs to the bone marrow and subsequent lodging in the HSC niche. The molecular mechanisms underlying bone marrow homing are, thus far, incompletely understood. This review focuses on recent studies that extended our understanding of how the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/c-akt) signaling module can regulate migration and homing of HSCs. Recent findings In addition to regulation of HSC maintenance and lineage development, it has recently become apparent that the PI3K/PKB signaling module plays a critical role in regulation of migration and adhesion of hematopoietic stem and progenitor cells. Activation of this signaling pathway enhances firm adhesion, reduces migration and inhibits bone marrow homing, whereas inhibition of PKB conversely induces bone marrow homing. Summary These findings clearly implicate the PI3K/PKB signaling module in playing a critical role in regulation of bone marrow homing, suggesting that pharmacological modulation of this signaling molecule prior to transplantation may provide a clinical means of improving engraftment levels and accelerating hematopoietic recovery.