Specific stages of angiogenesis are regulated by extracellular proteins. This review discusses the endogenous proteolysis of eight of these proteins and the release of polypeptide fragments that have biological activities different from those of the native, parent protein. The generation of natural cleavage products could provide a precise mechanism for the regulation of angiogenesis. Although further experimental confirmation of this mechanism is needed, this leitmotif offers an attractive explanation, in part, for the complex role of proteolysis in vascular morphogenesis.