Neuroendocrine neoplasms (NENs) represent a diverse collection of malignancies with heterogenous cell and tissue of origin, clinical behavior, and genetic underpinnings. This chapter explores the developmental basis of neuroendocrine cells, the genetics underlying tumorigenesis, and the downstream functional consequences of gene mutations. We further discuss the development and utility of preclinical models and integrate this knowledge in the context of advancing therapeutic options for these tumors.