A large body of preclinical work suggested that the epidermal growth factor receptor (EGFR) would be a successful target for therapy against non-small cell lung cancer (NSCLC), and this led to the development of oral, selective EGFR tyrosine kinase inhibitors (TKI) that improve symptoms and survival in patients with advanced NSCLC. However, not all patients benefit from this treatment, and there has been great interest in identifying the molecular correlates that predict for response to these agents. The recent detection of somatic mutations in EGFR that predict for response to the EGFR tyrosine kinase inhibitors has excited the scientific community. This discovery has far-reaching implications, not only for lung cancer patients treated with an EGFR TKI but also for future drug development in all malignancies.