Through a poorly understood mechanism, tumors respond to radiation by secreting cytokines capable of inhibiting apoptosis in endothelial cells, thereby diminishing treatment response by minimizing vascular damage. We reveal here that this pathway is governed by a major angiogenesis regulator, HIF-1. Following radiotherapy, tumor reoxygenation leads to: (1) nuclear accumulation of HIF-1 in response to reactive oxygen, and (2) enhanced translation of HIF-1-regulated transcripts secondary to stress granule depolymerization. The resulting increase in HIF-1-regulated cytokines enhances endothelial cell radioresistance. Inhibiting postradiation HIF-1 activation significantly increases tumor radiosensitivity as a result of enhanced vascular destruction. These data describe novel pathways contributing significantly to our understanding of HIF-1 regulation which may be major determinants of tumor radiosensitivity, potentially having high clinical relevance.