It is believed that impairments in delivery of antineoplastic agents to solid tumors result from abnormalities of the tumor microenvironment. Vascular endothelial growth factor (VEGF), the prototypical angiogenic molecule, is one of the main factors responsible for the development and maintenance of the aberrant tumor vascular network, which is characterized by chaotic, leaky blood vessels with high interstitial fluid pressure and inefficient blood flow. The authors proposed that anti-VEGF therapy would reduce the elevated interstitial fluid pressure in tumors, thereby improving blood flow and potentially improving delivery of cytotoxic agents to tumor cells. For the current report, the authors reviewed characteristics of the abnormal tumor vasculature created under the influence of VEGF, the resulting tumor microenvironment, how the tumor microenvironment may impede delivery of antineoplastic agents, and how the combination of anti-VEGF and cytotoxic therapy may maximize the efficacy of antineoplastic treatment regimens. Cancer 2005. © 2005 American Cancer Society.