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Radiotherapy plays a crucial role in the treatment of many malignancies; however, locoregional disease progression remains a critical problem. This has stimulated laboratory research into understanding the basis for tumor cell resistance to radiation and the development of strategies for overcoming such resistance. We know that some cell signaling pathways that respond to normal growth factors are abnormally activated in human cancer and that these pathways also invoke cell survival mechanisms that lead to resistance to radiation. For example, abnormal activation of the epidermal growth factor receptor (EGFR) promotes unregulated growth and is believed to contribute to clinical radiation resistance. Molecular blockade of EGFR signaling is an attractive strategy for enhancing the cytotoxic effects of radiotherapy and, as shown in numerous reports, the radiosensitizing effects of EGFR antagonists correlate with a suppression of the ability of the cells to repair radiation-induced DNA double strand breaks (DSBs). The molecular connection between the EGFR and its governance of DNA repair capacity appears to be mediated by one or more signaling pathways downstream of this receptor. The purpose of this review is to highlight what is currently known regarding EGFR signaling and the processes responsible for repairing radiation-induced DNA lesions that would explain the radiosensitizing effects of EGFR antagonists.