Over the past three decades, progress has been made in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Current recommendations include combination chemotherapy with or without targeted therapy. Despite these advances, the majority of patients relapse after initial treatment. Many of these patients are eligible for second-line therapy, which has prompted significant clinical research in this area. In 1999, docetaxel became the first drug approved by the US Food and Drug Administration for the treatment of patients with advanced NSCLC in the second-line setting. In 2004, two additional agents, pemetrexed and erlotinib, also received approval, giving patients three options for second-line treatment. Many promising new drugs and drug combinations are currently under investigation.