Up to 20% of lung adenocarcinomas in the United States and Europe and 50% in Asia have activating mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The identification and subsequent targeting of mutations with EGFR-tyrosine kinase inhibitors (TKIs) led to significant advances in treatment of EGFR-mutant lung cancer. Newer-generation EGFR-TKIs resulted in improvement in outcomes, with less toxic side effects and better tolerability. Resistance to EGFR-TKIs remains a significant barrier, and better understanding of resistance mechanisms is needed. Efforts are ongoing to incorporate targeted therapy into treatment of patients with earlier-stage disease.