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Endothelial cell invasion is an essential event during angiogenesis (the formation of new blood vessels). This process involves the degradation of the extracellular matrix, the basement membrane, and interstitial stroma, and is governed by the activation of matrix metalloproteinases. However, the contribution of matrix metalloproteinases in angiogenesis is much more complicated. Tumor growth above a certain size is dependent on new vessels. A number of studies have demonstrated that treating tumors with matrix metalloproteinase inhibitors results in tumor reduction and a decrease in tumor angiogenesis. Matrix metalloproteinases as sole matrix eaters or degraders is a matter of the past. Not only tumor cells but more importantly bystander cells such as stromal cells produce matrix metalloproteinases. Matrix metalloproteinases therefore are also part of the pathologic microenvironment in different diseases. This enzymatic microenvironment dictates the endothelial cell fate, the angiogenic switch, and finally angiogenesis. During recent years, the role of matrix metalloproteinases has expanded, and their function as modulators of biologically active signaling molecules has drawn much attention. Depending on their substrate (growth factors or their receptors, extracellular matrix components, and angiogenic factors), matrix metalloproteinase activation results in the generation of proangiogenic or antiangiogenic factors. These data challenge the old concept that matrix metalloproteinases are simply proangiogenic. The knowledge of the local enzymatic profile and what, where, and how matrix metalloproteinases are involved in angiogenesis of tumors or other diseases will help design future therapeutic strategies better reflecting the complexity of the underlying biologic process of angiogenesis.