Healthy cells, as well as benign and malignant tumors, depend upon the body's blood supply to bring in oxygen and nutrients and carry away waste products. Using this property against tumors, anti-angiogenic therapy targets the tumor vasculature with the aim of starving the tumor, and has demonstrated exceptional clinical efficacy against a number of tumors. This review discusses the current state of knowledge regarding anti-angiogenic therapies presently available to patients, and garners from both preclinical and clinical literature the benefits and side effects associated with anti-angiogenic therapies, the unfortunate mechanisms of acquired resistance to these novel therapeutics, and highlights promising next generation anti-angiogenics that may overcome the limitations encountered with first generation therapies. J. Cell. Biochem. 111: 543–553, 2010. © 2010 Wiley-Liss, Inc.