The therapeutic potential of targeting tumor endothelium and vascular supply is now widely recognized to treat different diseases. One such disease is cancer; where endothelial cells are actively proliferating to support the tumor growth. Solid tumors cannot grow beyond the size of a few millimeters without inducing the proliferation of endothelium and formation of new blood vessels. Hence it is crucial to search for new agents that selectively block tumor blood supply. These include anti-angiogenic molecules, vascular disrupting agents or endothelial disrupting agents. The anti-angiogenic molecules such as monoclonal antibodies and tyrosine kinase inhibitors disrupt endothelial cell survival mechanisms and new blood vessel formation, and vascular disrupting agents for instance ligand-directed and small molecules can be used to disrupt the already existing abnormal vasculature that support tumors by targeting their dysmorphic endothelial cells. The recent advances in this area of research have identified a variety of investigational agents which are currently in clinical development at various stages and some of these candidates are already approved in cancer treatment. This report will review some of the recent developments and most significant advances in this field and outline future challenges and directions.