Epidermal growth factor receptor (EGFR) overexpression is associated with resistance to chemotherapy andradiotherapy. The EGFR modulates DNA repair after radiation-induced damage through an association withthe catalytic subunit of DNA protein kinase. DNA double-strand breaks (DSBs) are the most lethal type of DNAdamage induced by ionizing radiation, and non-homologous end joining is the predominant pathway for repairof radiation-induced DSBs. Some cell signaling pathways that respond to normal growth factors are abnormallyactivated in human cancer. These pathways also invoke the cell survival mechanisms that lead to resistance toradiation. The molecular connection between the EGFR and its control over DNA repair capacity appears to bemediated by one or more signaling pathways downstream of this receptor. The purpose of this mini-review wasnot only to highlight the relation of the EGFR signal as a regulatory mechanism to DNA repair and radiationresistance, but also to provide clues to improving existing radiation resistance through novel therapies based onthe above-mentioned mechanism.