Angiogenesis is characterized by the development of new vasculature from pre-existing vessels and plays a central role in physiological processes such as embryogenesis, wound healing and female reproductive function, as well as pathophysiologic events including cancer, rheumatoid arthritis and diabetic retinopathy. The growth and metastasis of tumors is critically dependent upon angiogenesis. Although targeting angiogenesis as a therapeutic strategy has to date met with limited success in the clinic, the recent FDA approval of the anti-VEGF antibody Avastin has validated the use of anti-angiogenic therapeutic strategies for cancer treatment. We have recently identified several plasma proteins having anti-angiogenic properties, including Histidine-Proline-Rich Glycoprotein (HPRG) and activated high-molecular-weight kininogen (HKa). Both of these proteins are able to induce apoptosis in endothelial cells in vitro and can inhibit angiogenesis in vivo. Recent studies from our laboratories have also identified a novel cell-surface binding protein for HKa that mediates its anti-angiogenic activity. This protein, tropomyosin, is normally found inside the cell and is associated with the actin cytoskeleton, where it plays a critical role in stabilizing actin filaments in a variety of cell types. However, in angiogenic endothelial cells, tropomyosin appears to have extracellular localization. Previous studies have also suggested the involvement of tropomyosin in the anti-angiogenic activity of endostatin, and our recent work indicates that tropomyosin may mediate the antiangiogenic activity of HPRG as well. In this review, we summarize data describing extracellular tropomyosin as a novel receptor for multiple anti-angiogenic proteins. Extracellular tropomyosin may therefore represent a previously undescribed central target for the development of anti-angiogenic therapy.