Angiogenesis is an integral element of normal physiologic development as well as of wound healing and a variety of pathologic conditions. Since the earliest studies of the cellular processes required for the formation of new capillaries from preexisting vessels, proteolysis has been recognized as one of the earliest and most sustained activities involved in these events. Several proteases including matrix metalloproteases (MMPs), and the closely related ADAM (a disintegrin and metalloprotease domain) and ADAMTS (a disintegrin and metalloprotease domain with thrombospondin motifs) families, as well as cysteine and serine proteases, have been implicated in this regulation. The current review addresses the contribution of these proteases in the positive and negative regulation of angiogenesis as mediated by degradation of the endothelial basement membrane and extracellular matrix proteins, release of angiogenic factors, processing of cytokines, growth factors and growth factor receptors, and the production of endogenous inhibitors.