Despite advances in chemotherapeutics, overall survival for advanced lung cancer patients remains poor. Consequently, efforts have focused on the use of targeted therapies to improve response rates and survival. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of cancers, including lung, and may play a critical role in the pathogenesis of disease. Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa(R)), have response rates of between 10 and 27% in Phase II trials, and anecdotal reports of dramatic and sustained responses. Two recent studies published simultaneously, identified mutations in the ATP-binding cleft of the EGFR that are associated with clinical response to gefitinib. This finding has extraordinary implications and serves as a critical step toward individualized, patient-specific treatment plans based on the molecular constitution of the tumor of each individual.