The epidermal growth factor receptor (EGFR) is overexpressed and/or constitutively activated in a variety of human malignancies. Detection of increased expression levels of EGFR in cancer and the association between overexpression and decreased patient survival has led to the development of several therapeutic strategies to target this receptor. The results of early-phase clinical trials to date suggest that targeting EGFR alone may not be sufficient to eradicate established tumors. This limited antitumor efficacy as monotherapy has led to combining EGFR inhibitors with chemotherapy or radiation therapy for advanced disease, or incorporating EGFR inhibition to cancer prevention approaches. This review will discuss the role of EGFR signaling in carcinogenesis and the rationale for EGFR inhibition as a clinical prevention and treatment strategy.