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Overview: Hypoxia is the most cited biological topic in translational radiation oncology. The microenvironment of solid tumors is hypoxic compared with normal tissue, and this hypoxia is associated with decreased radiosensitivity. Irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, increasing tumor-infiltrating immune cells and causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. At present, various approaches have been investigated to support a high level of evidence for the benefit of hypoxic modification. We will highlight the biological rationale, and the current investigations, related to identifying and overcoming hypoxia in modern radiotherapy.