Although patients with advanced non-small cell lung cancer (NSCLC) cannot be cured, cytotoxic chemotherapy in patients with reasonable performance status can improve overall survival and quality of life. No one regimen has demonstrated superior efficacy results, and platinum-based doublets remain the current standard of care. The toxicity profiles of acceptable regimens differ, allowing treatment to be tailored to a specific patient. The duration of first-line chemotherapy should not exceed four to six cycles. Second- and third-line treatment regimens also have established survival benefits, which has led to increasing improvements in overall survival for patients with advanced NSCLC. Treatment approaches in patients with borderline performance status remain controversial. Although the optimal treatment approach for elderly patients has not yet been established, it is clear that the elderly do benefit from chemotherapy, and fit elderly patients can be treated with the same regimens as younger patients. It is critical that all patients with advanced NSCLC be referred to medical oncologists. Patients considering chemotherapy must have a clear understanding of the expected benefits, limitations, and toxicities.