Angiogenesis, the formation of new blood vessels, is required for many physiological processes, including organ/tissue maintenance (perfusion), and for pathological processes, including tumor growth/abnormal neovascularization at different sites. Angiogenesis is regulated by the activity of endogenous stimulators and inhibitors where the balance between endogenous angiogenesis stimulators and inhibitors is involved in the day-to-day process of regulating blood vessel formation. Endogenous inhibitors are often derived from the shedding of soluble receptors, extracellular matrix (ECM) or basement membrane proteins, endogenous anti-inflammatory, and anti-coagulants. An imbalance between the endogenous angiogenesis stimulators (increased levels and activity) and endogenous angiogenesis inhibitors (decreased levels and activity) or both would result in functional increase of endothelial migration and endothelial tube morphogenesis, with the net acceleration of the angiogenesis processes and vice versa. Angiogenesis inhibitors are relatively less toxic than conventional chemotherapy and represent a new class of anti-cancer agents. Several endogenous angiogenesis inhibitors have been discovered in the circulation and/or in the ECM acting at specific site (s). Examples of endogenous angiogenesis inhibitors include: Soluble VEGFR-1 (decoy receptor for VEGF-B and PIGF); Angiopoietin 2 (antagonist of angiopoietin 1); Thrombospondin; Angiostatin; Endostatin; Vasostatin; Platelet Factor 4; Tissue Factor Pathway Inhibitor; Heparin and Kininogen fragments; and several other ECM fragments. Several endogenous angiogenesis inhibitors and pharmacological inhibitors of endogenous pro-angiogenesis switches have been developed and approved for clinical uses alone and in combinations with other agents such as chemotherapy. Examples of such agents include bevacizumab, which was the first angiogenesis inhibitor shown to slow tumor growth and, more importantly, to extend the lives of patients with some cancers. The FDA has also approved other drugs that have anti-angiogenic activity, including sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), and everolimus (Afinitor®). Sorafenib is approved for hepatocellular carcinoma and kidney cancer, sunitinib and everolimus for both kidney cancer and neuroendocrine tumors, and pazopanib for kidney cancer. The use of other novel angiogenesis inhibitors (integrin antagonists, Nanotechnology-based targeted strategies (Nanotetrac) to treat other types of cancer and others disorders that involve the development of abnormal blood vessel growth such as diabetic retinopathy, macular degeneration, and other vascular-associated disorders, are advancing into clinical development.