NSCLC is the leading cause of cancer mortality in the United States. Approximately 30-40% of patients present with advanced stage disease (Stage IIIb with malignant effusion and Stage IV) and the majority of those who present with "earlier" disease will ultimately develop and succumb to metastatic lung cancer. Although platinum-based combination chemotherapy has been shown to impact overall survival and quality of life, it is not curative and less than 25% of patients survive 2 years. Therefore, the benefits of chemotherapy must be weighed against toxicity, inconvenience, and cost. Several randomized trials have shown that there is no added benefit of extending first line, platinum-based chemotherapy beyond four cycles. There was no additional survival benefit and patients experienced increased toxicity with longer durations of therapy. Attempts to improve outcome by planned sequential therapy, i.e. shifting from one cytotoxic regimen to another after a fixed number of cycles have also not been successful. Several new so-called "targeted" therapeutic agents have recently been evaluated in clinical trials to assess whether the efficacy of first line chemotherapy with platinum doublets can be improved with the addition of these agents. These include bevacizumab, epidermal growth factor receptor inhibitors (erlotinib and gefitinib), bexarotene, matrix metalloproteinase inhibitors, and others. Other than bevacizumab, none have demonstrated benefit in this scenario. The design of most of these trials employed the concurrent use of the new agent with six cycles of platinum-based chemotherapy (usually either carboplatin/paclitaxel or cisplatin/gemcitabine) and then continued the new agent until relapse. Three agents have demonstrated benefit in randomized studies in the second line setting, docetaxel, pemetrexed, and erlotinib. No study has evaluated the optimal duration of therapy for these agents, though for erlotinib, it appears that use until progression is optimal. Future studies of novel agents will need to explore not only the potential use of these agents in combination or in comparison with standard therapy, but also the duration of therapy and consider issues of survival, quality of life, and cost.