Blood vessels connect all districts of the body and allow blood oxygen and nutrients to reach every cell in the organism. Dysregulation of blood vessel formation or functionality is the origin of a large number of diseases. During new vessel formation, endothelial cells degrade their basement membrane, migrate into the interstitial matrix and proliferate. Migrating endothelial cells need to be polarized, to focus at their leading edge the proteolytic machinery, which is essential for extracellular matrix degradation; thus, proteases and their receptors play a crucial role in angiogenesis. The urokinase-mediated plasminogen activation system is a complex system of serine proteases strongly involved in angiogenesis. The plasminogen activation system includes plasminogen/plasmin, activators, inhibitors and cell receptors. In the last decades, a large body of evidence has clearly indicated that the role of this system is not limited to extracellular matrix proteolysis but can contribute to all phases of the angiogenic process.