Pancreatic neuroendocrine neoplasms include mainly well-differentiated neuroendocrine tumors but also rare poorly differentiated neuroendocrine carcinomas. Molecular mechanisms underlying pancreatic neuroendocrine tumorigenesis have recently been elucidated. While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly differentiated neuroendocrine carcinomas. With these discoveries, new molecular targeted therapies have become available and show promise in some patients with pancreatic well-differentiated neuroendocrine tumor.