EGF receptor (EGFR) activation has an important role in various steps of carcinogenesis and progression of non-small-cell lung cancer (NSCLC), implying that EGFR is a potential target for cancer therapy. Therefore, targeted treatments aimed at EGFR have been developed, of which tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib have shown activity in NSCLC. The unexpected findings of a lack of association between expression of EGFR, the target and efficacy of EGFR TKIs and higher response in selective subgroups of patients were puzzling. Identification of somatic activating mutations in the EGFR tyrosine kinase domain solved the mystery and provided new insight. Several lines of study provided information on various molecular targets for EGFR TKI therapy. A target-based patient-selection strategy is expected to eventually lead to tailored therapy for lung cancer.