Pancreatic neuroendocrine tumors (PNETs) share a unique genetic identity, functional behavior, and clinical course. Compared with tumors of the exocrine pancreas, they are rare and show a different biologic behavior and prognosis. On the basis of data from recent studies, all PNETs, outside of small insulinomas, should be considered potentially malignant and treated accordingly. Untreated tumors have a high possibility to grow locally into adjacent structures or spread to distant organs. Although surgical excision irrespective of tumor functioning or nonfunctioning state remains the cornerstone of therapy, providing the best disease-free and survival rates to date, the understanding of the genetic nature of the disease yields new 'targets' to consider in drug development. The aim of this review is to summarize all recent advances of genetic research and new drug development in terms of PNETs, especially their genetic identity and subsequent alterations leading to the development of near or total malignant activity, and the new medical treatment strategies of this potentially curable disease on the basis of therapeutical agents acting, where possible, at the genetic level.