Radiation is used to treat a variety of tumors and the response of tumors to radiation is dependent on endothelial cell death, which in turn limits oxygen delivery to the tumor, causing hypoxia and tumor cell death. Recently, radiation-induced hypoxia was shown to trigger tumor resistance to radiation via the activation of new blood vessel formation (angiogenesis) through molecules known as HIF-1-regulated cytokines. In a study appearing online on June 7 in advance of publication in the July print issue of the Journal of Clinical Investigation, Claire Magnon and colleagues from Institut Gustave Roussy, France, show that a combination of radiation treatment and the use of angiogenesis inhibitors such as canstatin is able to overcome HIF-1-dependent tumor survival pathways and increases tumor cell death. The authors found that following application of this dual therapy to mice, HIF-1alpha increased the activity of the canstatin-induced tumor apoptotic pathway, which lead to lethal tumor damage. The study demonstrates a crucial role for angiogenesis inhibitors in shifting tumor radioresistance towards tumor apoptosis and suggests that a combination of radiation and angiogenesis inhibitors could potentially be used to overcome HIF-1-dependent tumor radioresistance.