Non-small-cell lung cancer (NSCLC) is a major global health problem and is the leading cause of cancer death worldwide. Current treatment involves nonspecific, nonselective cytotoxic chemotherapy, which results in only a modest increase in survival and causes significant toxicity to the patient. Targeted agents are initially effective in certain small subpopulations of patients, but eventually nearly all patients become resistant to further treatment. The limitations in efficacy and safety associated with available treatments for NSCLC underscore the need for novel agents with improved efficacy and safety profiles. This review discusses the limitations of currently recommended therapies for patients with advanced NSCLC and discusses new agents in clinical development for this disease.