Angiogenesis is the formation of new microvessels from existing vasculature. It is a crucial component of normal embryogenic development and of some physiological processes in adulthood. Pathological conditions such as tumor growth and metastasis, which involve tissue remodeling and inflammation, are usually associated with vascular leakage and subsequent angiogenesis. Tumor angiogenesis often augments tumor survival, progression, and metastasis, thus enhancing the malignant characteristics of the disease. Proteolytic degradation of the extracellular matrix that surrounds both the capillary sprouts and the migrating tumor cells is an essential part of tumor angiogenesis and tumor growth. In particular, proteases of the fibrinolytic system and the matrix metalloproteinase family play a role in these processes. In addition to proangiogenic effects, proteases also can negatively regulate angiogenesis. Protein fragments that result from proteolytic degradation of extracellular matrix components and other proteins can exhibit potent antiangiogenic properties. A thorough understanding of tumor-associated proteolytic processes is required to identify specific targets that are suitable for protease-based tumor therapy.