Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Standard treatment approaches such as chemotherapy, radiotherapy, and surgery have reached a plateau in this disease. Therefore, alternatives to conventional treatment, such as new molecular-targeted therapies, are needed. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. There are two EGFR tyrosine kinase inhibitors approved for the treatment of advanced NSCLC: gefitinib and erlotinib. Of these, erlotinib has shown a significant improvement in median survival, quality of life, and related symptoms in an unselected population of advanced and metastatic NSCLC patients in the second- or third-line setting. Furthermore, erlotinib has significant antitumor activity in first-line treatment. Moreover, factors that predict the efficacy of erlotinib, including clinical, pathologic, and molecular features, have been investigated. A series of studies is planned to contribute to our understanding of the role of erlotinib in NSCLC treatment. Major areas of clinical research are the assessment of erlotinib: in adjuvant treatment, combined with chemotherapy and/or radiotherapy in locally advanced disease, in the first-line therapy of advanced disease, and in combination and/or sequence with cytotoxic treatments and/or other molecular target agents.