Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa), have shown remarkable activity in a portion of patients with non-small-cell lung cancer (NSCLC). Based on a large randomized controlled trial showing a survival benefit compared with placebo, erlotinib gained US Food and Drug Administration approval for use in previously treated patients with NSCLC. However, its use in the first-line setting has been largely experimental. Recently, a large phase III randomized controlled trial demonstrated the superiority of first-line gefitinib therapy compared to combination chemotherapy in a clinically selected population consisting of Asian patients with adenocarcinoma and a light smoking history. This result was even more dramatic in the subset of patients whose tumors carried a mutation in the EGFR gene. Currently, randomized phase III trials of erlotinib as initial treatment of patients with EGFR mutant lung cancer are ongoing. In the setting of these recent developments, a review of the data regarding the use of erlotinib or gefitinib as initial therapy in the treatment of NSCLC is warranted. Currently active trials are referenced using their ClinicalTrials.gov identifier.