Sensitivity to radiation and chemotherapy can be influenced by factors extrinsic to the cancer cell. For example, severely hypoxic cells require 2-3 times the radiation dose as do well-oxygenated cells to achieve similar cell killing. Apart from the tumor cells, neighboring cells such as endothelial cells may influence radiosensitivity. Irradiation can lead to expression of molecules that may increase radio/chemoresistance, for example vascular endothelial growth factor (VEGF), a secreted protein that regulates angiogenesis, or hypoxia inducible factor-1α (HIF-1α), a master transcription factor that regulates gene expression in hypoxia. Hence, response to cytotoxic therapy may be improved by modulating the tumor microenvironment (TME). Several agents in clinical use may do this. Some of these target vasculature, either directly or indirectly by disrupting VEGF and/or HIF-1 signaling. Many of these agents have been shown to increase radio/chemosensitivity in preclinical models. A confounding factor in terms of radiosensitization is the variable effect of these drugs on tumor oxygenation. Some of these agents ablate the vasculature, thereby increasing hypoxia. Others may normalize tumor vasculature, leading to increased blood flow and oxygenation, thereby potentially increasing radiosensitivity and the delivery of chemotherapy. Inhibitors of EGFR signaling and the PI3K/Akt pathway can also cause similar vascular changes in preclinical models, perhaps by indirectly inhibiting VEGF secretion. In summary, agents are currently available in the clinic that might modulate the TME in a way that could improve radio/chemosensitivity. The challenge is to show that this occurs in human patients and then use this information to optimize cancer therapy.