Grade 3 neuroendocrine neoplasms (NEN G3) are high-grade (Ki-67 index >20%) neuroendocrine malignancies that comprise both rapidly proliferating, well-differentiated neuroendocrine tumors (NET G3) and poorly differentiated neuroendocrine carcinomas (NEC). The phenotypic differences between NET G3 and NEC stem from differences in their underlying genomic alterations. As a result of these differences, NET G3 is molecularly, radiologically, and prognostically distinct from NEC. The optimal management of NET G3 and NEC is currently being refined through clinical trials that focus on NET G3 and NEC as separate entities. This review aims to summarize the current understanding of NEN G3 by distinguishing between NET G3 and NEC and describing the clinical implications associated with each.