The epidermal growth factor receptor (EGFR) has emerged as a central molecular target for modulation in cancer therapeutics, since EGFR signaling affects many factors that in turn promote tumor growth, progression and metastasis. In addition, radiobiological investigations have also defined a critical role for EGFR in mediating cytoprotective and pro-proliferative responses in human cancer cells after ionizing radiation, that contribute at least in part to accelerated tumor cell repopulation. This led to the additional development of EGFR as a target to enhance radiation efficacy. Several anti-EGFR strategies have been put forth demonstrating a favorable biological interaction between EGFR blockade and radiation. However, further preclinical investigations are necessary to better explore mechanisms of action and efficacy of combined treatment modalities. Although some of the anti-EGFR approaches have already reached clinical testing in combination with radiation, it is still too early to establish a clinical proof for the ultimate role of EGFR inhibition in combination with radiation. This article focuses primarily on anti-EGFR approaches to modulate radiation response.