Non-small-cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Traditional cytotoxic agents and their attendant toxicities have remained the mainstay of systemic therapy for this disease, until now. With the identification of novel molecular and immune cancer-specific aberrancies, molecular agents and immunotherapies have garnered increasing attention as attractive targets, with the potential for improved outcomes while mitigating systemic toxicities seen with traditional cytotoxic agents. Despite a longstanding interest in immunotherapy for the treatment of NSCLC, results of prior studies of therapeutic vaccines have failed to show durable or convincingly meaningful clinical responses. However, newer trials of therapeutic vaccines and checkpoint inhibitors have yielded more promising results. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown meaningful clinical responses with manageable toxicities. Large phase III studies are underway, the results of which have the potential to revolutionize the way in which we care for patients with NSCLC. More studies also are needed to investigate the potentially synergistic effects of traditional and immune-based therapies. Given their unique antineoplastic effects, novel immune-specific clinical endpoints also are actively being investigated.