Tumor growth depends upon access to host blood vessels. Many steps in tumor angiogenesis have been defined including tumor cell hypoxia, tumor cell secretion of pro-angiogenic growth factors, receptor activation on host endothelium and stroma, and establishment of new blood vessels feeding the tumor mass. Inhibitors for some of these steps have been synthesized and tested clinically. While modest improvements in response, progression-free survival and overall survival have been observed in metastatic colorectal carcinoma, non-small cell lung carcinoma, breast carcinoma, renal cell carcinoma, and glioblastoma, almost all patients ultimately relapse and die from metastatic disease. Explanations for the limited effects of anti-angiogenesis therapy include lack of activity on all the parallel angiogenic pathways, non-specific toxicities of some of the agents, induction of a pro-metastatic phenotype by the enhanced hypoxia from therapy, and lack of effect on already established tumor blood vessels. One solution is to directly attack the tumor vasculature rather than inhibit tumor vessel formation. The flavonoid ASA404 and the tubulin-binder combretastatin A-4 phosphate directly damage tumor endothelium by different mechanisms. Both compounds have shown minimal single agent disease activity and produce cardiac ischemia in clinical trials. Recently, ligand-directed vascular disrupting agents have been synthesized and tested. A promising member of this class of therapeutics targets the tumor endothelial marker-8 (TEM8). Anti-TEM8 antibody drug conjugate may facilitate selective destruction of tumor blood vessels yielding enhanced anti-cancer efficacy and reduced normal tissue toxicities. Advances in this field are described which should lead to clinical studies of TEM8 targeted cancer therapeutics.