Growth factors are a group of proteins that regulate a wide variety of cellular processes, including proliferation, differentiation, motility, adhesion, and apoptosis of target cells. They play crucial roles in the formation and maintenance of tissue architecture in embryonic development and adult tissue homeostasis. Because aberrations in growth factor signaling often result in pathological conditions, the activities of growth factors are tightly controlled by extracellular and intracellular regulators. Hepatocyte growth factor (HGF) is a mesenchymal cell-derived growth factor that affects various target cells, including epithelial and endothelial cells. HGF is synthesized and secreted as a latent form, and is proteolytically activated in response to tissue injury, thus participating in tissue regeneration and repair. Interestingly, HGF has a unique structural feature: it is homologous to plasminogen, a key enzyme in the fibrinolytic system. Elucidation of the regulatory mechanisms of HGF activity has revealed that a blood coagulation factor XII-like serine protease, hepatocyte growth factor activator, efficiently converts HGF from the latent form to the active form. Hepatocyte growth factor activator itself is activated downstream of the blood coagulation cascade, and links tissue injury to activation of HGF. HGF thus has structural as well as functional relevance to the blood coagulation/fibrinolytic system.