Epidermal growth factor receptor (EGFR) is considered to be one of the key driver genes in non-small celllung cancer (NSCLC). Several clinical trials have shown great promise of EGFR tyrosine kinase inhibitors (TKIs)in the first-line treatment of NSCLC. Many advances have been made in the understanding of EGFR signaltransduction network and the interaction between EGFR and tumor microenvironment in mediating cancersurvival and development. The concomitant targeted therapy and radiation is a new strategy in the treatment ofNSCLC. A number of preclinical studies have demonstrated synergistic anti-tumor activity in the combinationof EGFR inhibitors and radiotherapy in vitro and in vivo. In the present review, we discuss the rationale of thecombination of EGFR inhibitors and radiotherapy in the treatment of NSCLC.