It is well known that hematopoietic stem/progenitor cells (HSPC) circulate in peripheral blood (PB) under steady-state conditions at very low levels to maintain a pool of stem cells in balance in the bone marrow (BM) microenvironment present in bones throughout the body. Therefore, PB could be envisioned as a “highway” by which HSPCs relocate in the organism between hematopoietic endosteal and endothelial niches usually located in distant bones. It has been calculated that in mice, approximately 400 HSPCs circulate at any given moment in the PB. In addition, recent evidence suggests that while circulating in PB, HSPCs may enter tissues and return back to the PB via the lymphatic system and thoracic duct. This route of “circulation/ tissue patrolling” is enforced during infection, in which circulating HSPCs mobilized during infection could be recruited to the affected peripheral tissues and give rise to tissue-resident myeloid and dendritic cells. This mechanism is thus an important part of innate immunity surveillance under steady-state conditions and is enhanced in response to inflammation or organ injuries (e.g. heart infarct, or stroke). The enforced migration of HSPCs from BM into PB is called mobilization and can be induced by some pharmacological agents. From a clinical point of view it is an important procedure that provides HSPCs for hematopoietic transplantation. On the other hand, the migration of HSPCs from PB (after HSPC transplantation) into BM is called homing which is crucial for repopulating the whole blood cells. Complement cascade (CC) as a part of innate immunity emerges as important and underappreciated modulator of trafficking of HSPC. Accordingly, we reported that (i) C becomes activated in BM during G-CSF-induced mobilization by the classical immunoglobulin (Ig)- dependent pathway, (ii) C1q and C3 cleavage fragments increase the responsiveness of HSPC to an stromal derived factor-1 (SDF-1) gradient, indicating that these C fragments increase HSPC homing and (iii) in contract, C5a disrupts the HSPC retention in the BM leading to egress of HSPCs and granulocytes into the PB and causing HSPC mobilization. Thus, in light of these findings, mobilization of HSPC could be envisioned as a part of an immune response that requires CC activation. Hence modulation of CC activation could allow for the development of more efficient mobilization strategies in patients who are poor mobilizers.