Angiogenesis is an essential step in the growth and spread of solid tumors--the cause of more than 85% of cancer mortality. Inhibiting angiogenesis would therefore seem to be a reasonable approach to prevent or treat cancer. However, tumor angiogenesis differs from normal angiogenesis in that the resulting vessels are tortuous, irregularly shaped, and hyperpermeable. These abnormalities result in irregular blood flow and high interstitial fluid pressure within the tumor, which can impair the delivery of oxygen (a known radiation sensitizer) and drugs to the tumor. Emerging evidence suggests that antiangiogenic therapy can prune some tumor vessels and normalize the structure and function of the rest, thereby improving drug delivery and normalizing the tumor microenvironment. This normalization effect may underlie the therapeutic benefit of combined antiangiogenic and cytotoxic therapies. This paper reviews current and emerging concepts of the mechanism of action of antiangiogenic therapies and discusses the implications of these mechanisms for their optimal clinical use.