Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebocontrolled phase III trials using 2 drugs-everolimus and sunitinib-with distinct molecular rationales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defining the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting. Summary: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies. © 2011 American Association for Cancer Research.