All acknowledge the importance of endothelial migra-tion and proliferation in angiogenesis. However, the sprouting of extensions of established vascular channels in most tissues requires much more. The extracellular space does not consist of a vacuum, permitting free spread of endothelial sprouts during angiogenesis. Rather, a complex and often dense extracellular matrix invests the parenchymal cells and microvascular channels of most organs. The endothelial cells must penetrate this extracellular matrix to make a new vessel (Figure 1A). Immediately surrounding the endothelial cells, a basement membrane of type IV collagen, laminin, fibronectin, and many other matrix macromolecules presents the first obstacle to neovascular sprout formation (Figure 1B). That barrier breached, the nascent microvessel must then burrow through collagen fibrils, elastin, microfibrillar proteins, proteoglycans, and other constituents of the surrounding extracellular matrix (Figure 1C). How do the endothelial cells drill their way through these layered impediments to form a new vessel?