Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.