The treatment of patients with hematopoietic progenitor and stem cells (HPSCs) to reconstitute hematopoiesis after myeloablative therapy or to repair ischemia after myocardial infarction has significantly improved clinical outcomes. Successful blood or bone marrow transplants require a sufficient number of HPSCs capable of homing to the injured site to regenerate tissue. Granulocyte-colony stimulating factor (G-CSF) is widely used clinically for stem cell mobilization. However, in some patients the response is poor, thus a better understanding of the mechanisms underlying G-CSF-regulated stem cell mobilization is needed. The pasminogen (Plg) system is the primary fibrinolytic pathway responsible for clot dissolution after thrombosis. Recent evidence suggests that Plg plays a pivotal role in stem cell mobilization from the bone marrow to the peripheral circulation, particularly in HPSC mobilization in response to G-CSF. This paper will discuss the potential mechanisms by which the Plg system regulates stem cell mobilization, focusing on stepwise proteolysis and signal transduction during HPSC egress from their bone marrow niche. Clear elucidation of the underlying mechanisms may lead to the development of new Plg-based therapeutic strategies to improve stem cell mobilization in treating hematological and cardiovascular diseases.