Migratory capacity is a fundamental property of hematopoietic stem and progenitor cells (HSPCs). This feature is employed in clinical mobilization of HSPCs to the circulation and constitutes the basis for modern bone marrow (BM) transplantation procedures which are routinely used to treat hematological malignancies. Therefore, characterization of new players in the complex process of HSPC motility in steady-state conditions as well as during stress situations is a major challenge. We report that while the metalloproteinase membrane type 1-metalloprotease (MT1-MMP) has an essential role in human HSPC trafficking during granulocyte colony-stimulating factor (G-CSF)-induced mobilization, its inhibitor reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and the adhesion molecule CD44 are required for HSPC retention to the BM in steady-state conditions. The nervous system via Wnt signaling along with HGF/c-Met signaling and the complement cascade play a major role in regulating MT1-MMP increased activity, CD44 cleavage, and RECK-reduced expression during G-CSF-induced mobilization. This review will elaborate on the opposite roles of MT1-MMP and RECK in HSPC migration and retention and suggest targeting them in order to facilitate HSPC mobilization and engraftment upon BM transplantation in patients.