Lung cancer is the leading cause of cancer death in both men and women in the United States, and male Veterans seeking care at VA hospitals have a much higher age-specific incidence of lung cancer than males in the general population. The personal and economic significance of lung cancer has led to a vast research endeavor to try and identify new and more effective treatments. Until recently, all therapies for advanced NSCLC were based on their cytotoxic properties. In the last few years, several novel agents aimed at specific molecular targets have been developed. This review was requested to evaluate the current evidence on the effectiveness and cost-effectiveness of treatments for advanced lung cancer. Most patients with lung cancer are diagnosed when the cancer is already advanced (stage III or IV), and they are no longer candidates for surgical resection. Small cell lung cancer and nonsmall cell lung cancer (NSCLC) are treated as different diseases in terms of therapy. In the last few years, several novel agents aimed at specific molecular targets have been developed. This review was requested to evaluate the current evidence on the effectiveness and cost-effectiveness of treatments for advanced NSCLC. The key questions were: Key Question #1. For patients with metastatic non-small cell lung cancer (NSCLC) what is the comparative effectiveness of the different recommended (e.g. NCCN guidelines) first line chemotherapy regimens? Key Question #2. For patients with metastatic NSCLC what is the comparative effectiveness of the different recommended (e.g. NCCN guidelines) second line chemotherapy regimens? Key Question #3. For patients with metastatic NSCLC what is the benefit of maintenance therapy following first line chemotherapy regimens compared with no maintenance therapy? Key Question #4. What is the relative cost and cost-effectiveness of the different approaches in Key Questions 1-3?