The diagnosed incidence rate of neuroendocrine tumors (NETs) is on the rise. Prevalence calculations show NETs to be more common then previously thought. Although generally thought to be indolent, advanced NETs remain incurable and are resistant to most cytotoxic agents. The available biologic agents have limited activity against these tumors. Novel and active agents are clearly needed. The recent emergence of molecularly targeted therapy in oncology has brought renewed interest in the development of novel agents for this group of diseases. This paper will review the molecular biology of NETs, promising novel targeted therapy approaches including agents targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways, as well as pivotal phase III studies that may set new standards of care for this disease.