Gefitinib and erlotinib are small molecules that selectively inhibit epidermal protein receptor (EGFR) tyrosine kinase activity. When these drugs were introduced into the clinic, the precise targets affected in human tumors were unknown. In April 2004, two groups reported that mutations within the tyrosine kinase domain of EGFR are strongly related to gefitinib sensitivity in patients with non–small-cell carcinoma (NSCLC). We subsequently extended these findings and showed that such mutations also are related to sensitivity to erlotinib. Here, we present current knowledge about EGFR mutations within the context of clinical trials involving gefitinib and erlotinib in NSCLC.