Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. In the last decade the EGF receptor (EGFR) signaling pathway has emerged as one of the most important molecular aberrations in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR-TKI), such as erlotinib or gefitinib, demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harboring activating mutations of the EGFR gene. Results of large Phase III randomized trials clearly demonstrated that an EGFR-TKI is the best front-line option for patients with classical EGFR mutations, while in the EGFR wild-type or EGFR unknown population platinum-based chemotherapy remains the gold standard. In pretreated patients, EGFR-TKIs are considered more effective than standard chemotherapy in the EGFR-mutated population, with no difference in EGFR wild-type NSCLC. Although EGFR-TKIs are certainly particularly effective in patients with EGFR mutations, at present no biomarker, including KRAS mutations, can be recommended in clinical practice for precluding the therapy to any pretreated patient. In this article, the authors analyzed data of erlotinib in NSCLC, focusing on its role in front-line therapy.