Thrombospondin (TSP)-1 and -2 are potent inhibitors of angiogenesis in vivo and of microvascular endothelial cell responses to angiogenic factors in vitro. The anti-angiogenic activity of thrombospondins is contained in a structural domain known as the TSP type I repeat or TSR. TSR domains are present in many other proteins, several of which have also been shown to have anti-angiogenic activity and a peptide-mimetic drug based on the domain is in clinical trials as an anti-angiogenic anti-cancer therapy. We have identified CD36 as the endothelial cell receptor for TSP-1 and -2 and showed that it is necessary for their anti-angiogenic activity. CD36-mediated anti-angiogenic activity in endothelial cells is due to its ability to activate a specific signaling cascade that results in diversion of a pro-angiogenic response to an apoptotic response. Recently we identified a circulating protein, histidine-rich glycoprotein (HRGP), that contains a CD36 homology domain and that acts as a soluble decoy to block the anti-angiogenic activities of TSPs, thereby promoting angiogenesis. The tripartite interactions among CD36, TSR domains and HRGP in tissues may play an important role in regulating physiological and pathological angiogenesis.