Treatment of stage IV non-small cell lung cancer (NSCLC) is based upon chemotherapy, with several meta-analyses showing an improvement of survival compared to supportive care alone. For first-line chemotherapy, the development of new third generation drugs (vinorelbine, gemcitabine, paclitaxel, docétaxel) with a better therapeutic index has led to the definition of 4 to 6 cycles of a platinum-based dual agent regime as standard therapy for performance stage (PS) 0-1 patients, producing a 1-year survival in the region of 35%. The choice of agents is based upon the differences in the toxicity profile of platinum-based combinations and on patient co-morbidities. For frail patients (PS>2 and elderly patients), single-agent chemotherapy seems more appropriate than cisplatin-based combinations; carboplatin or non-platinum combinations might be more effective. Third generation cytotoxic agents have modestly improved survival for patients with stage IV NSCLC but should probably provide an increased number of long-term survivors.