As diagnostic and therapeutic options increase, strategies for the treatment of non-small-cell lung cancer (NSCLC) are becoming more tailored for specific patient subpopulations and individual patients. The introduction of therapy targeted against the EGF receptor (EGFR) pathway has provided new treatment options for select patients with NSCLC. However, more than half of unselected NSCLC patients will fail to achieve disease stabilization on an EGFR tyrosine kinase inhibitor (TKI), and secondary resistance is observed in virtually all patients who initially respond or achieve disease stabilization. Efforts are underway to identify clinical and molecular predictors in patients who may benefit from treatment with EGFR TKIs. Recent strategies for targeting the EGFR pathway include combining EGFR TKIs with newer agents and developing second-generation irreversible EGFR TKIs, which may be used in patients who have failed treatment with first-generation EGFR TKIs.