Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis in vivo and of microvascular endothelial cell responses to angiogenic factors in vitro. CD36 is the cellular receptor for TSP-1 on microvascular endothelium and is necessary for its anti-angiogenic activity. The anti-angiogenic activity of TSP-1 is contained in a structural domain known as the TSP type I repeat (TSR-1). TSR-1 domains occur in many other proteins, some of which have also been shown to have anti-angiogenic activity. Structure-function analyses have determined that binding of TSP-1 to CD36 is mediated by interaction of the TSR-1 domain of TSP with a conserved domain called CLESH-1 in CD36. Histidine rich glycoprotein, a plasma and cellular protein that blocks the binding of thrombospndin-1 to CD36, inhibits the antiangiogenic response to thrombospondin and may serve to modulate the thrombospondin/CD36 anti-angiogenic pathway. Several in vivo models support the role of the TSP/CD36 system in angiogenesis and tumor growth and provide evidence that the CD36 antiangiogenic pathway offers attractive therapeutic targets.