Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.