Lung cancer is the leading cause of cancer-related death among men and women in the United States. Approximately 80-85% of lung cancer cases are non-small-cell lung cancer (NSCLC), and approximately 65% of these patients have advanced-stage (IIIB/IV) disease at diagnosis. The median survival for patients with advanced-stage NSCLC treated with platinum-based chemotherapy is a disappointing 8-10 months. This article reviews the current status of chemotherapy in patients with a good functional status and evaluates the treatments in terms of efficacy, toxicity, survival, and impact on quality of life in the first-line treatment. Biologic agents such as bevacizumab and erlotinib have been investigated in phase III trials in the first- and second-line setting. These agents could play a role in select patient populations. This article also highlights some of the more promising new strategies, such as advances in pharmacogenomics and immune-based therapy. There is a clear need for improvement in the current standard of care. Well-designed clinical trials with appropriate patient selection, as well as continued efforts in translational research and pharmacogenomics, are crucial for progress in this disease.