Chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Over the past 20 years, advances in chemotherapy have shown minimal incremental improvement in the survival outcomes of patients with advanced NSCLC. With the identification of molecular and genetic alterations in lung cancer, several new potential rationally designed therapeutic targets have emerged. One of these is the epidermal growth factor receptor (EGFR) and member of the ErbB family of receptor tyrosine kinases. Several inhibitors, both antibodies directed at the extra-cellular portion of the receptor, and small molecule inhibitors directed at the tyrosine kinase domain of EGFR are in clinical development in lung cancer. This article will review the pre-clinical rationale and the clinical studies of EGFR inhibitors alone and/or in combination with chemotherapy that have been performed to date in advanced NSCLC.