Angiogenesis is a complex, multifactorial process that involves signals from endothelial cells and from the stoma. Extracellular matrix proteins participate in the modulation of growth factor response, contribute to the architecture of the vasculature and provide signals for the stabilization of mature capillary beds. The identification of the relevant extracellular matrix molecules and the characterization of their effects has been a central focus of research in vascular biology. Thrombospondin-1 is an extracellular glycoprotein first to be recognized as an inhibitor of angiogenesis more than a decade ago. Since then, much has been learned about its ability to regulate vascular growth in several angiogenesis models, functional domains have been identified, and mechanisms of action determined. This review summarizes current understanding on the effects of thrombospondin-1 and -2 during the process of angiogenesis. We will also extend our comments to ADAMTS1, a member of a relatively novel group of matrix metalloproteinases with thrombospondin repeats and shown to affect endothelial cell function and angiogenesis.