Neoangiogenesis, the formation of new blood capillaries from pre-existing vessels, plays an important role in a number of physiological and pathological processes, particularly in tumor growth and metastasis. Extracellular proteolysis by matrix metalloproteinases or other neutral proteinases is an absolute requirement for initiating tumor invasion and angiogenesis. Cryptic segments or pre-existing domains within larger proteins, most of them belonging to the extracellular matrix, can be exposed by conformational changes and/or generated by partial enzymatic hydrolysis. They can positively or negatively regulate important functions of endothelial cells including adhesion, migration, proliferation, cell survival and cell-cell interactions. Such regulations by cryptic segments and proteolytic fragments led to the concept of matricryptins and matrikines, respectively. Matrix metalloproteinases and matrikines in conjunction with other pro- or anti-angiogenic factors might act in concert at any step of the angiogenesis process. A number of matrikines have been identified as potent anti-angiogenic factors, which could provide a new alternative to anti-proteolytic strategies for the development of anti-angiogenic therapeutic molecules aimed at inhibiting tumor growth and metastasis. Some of them are currently being investigated in clinical trials.