Non-small cell lung cancer (NSCLC), which represents the bulk of primary carcinomas of the lung, is an aggressive malignancy. The majority of patients with NSCLC present with advanced disease, not curable by surgery, at the time of diagnosis. Recent randomized trials have shown an improvement in survival for patients with loco-regional disease treated with combination, platinum-based, chemotherapy and curative irradiation. Similarly, randomized studies of good performance status patients with metastatic disease have documented a survival advantage, albeit a modest advantage, for those receiving chemotherapy. New chemotherapy agents with activity in NSCLC have been studied in phase II trials. These agents need to be evaluated, in loco-regional and metastatic disease, in large randomized phase III trials before conclusions can be drawn about their role in treatment. Novel treatments which among other include gene therapy, anti-angiogenic and anti-metastatic agents are currently being assessed in early phase I and II studies. Gene therapy will likely be combined with standard chemotherapy and radiation in the treatment of NSCLC, whereas anti-angiogenic and anti-metastatic agents may play a role in prevention and maintenance therapy. Finally, regardless of the approach or modality, new interventions will need to be assessed for their impact on overall survival and the quality of life of patients with NSCLC.