Gastroenteropancreatic (GEP) neuroendocrine neoplasms are classified as low‐grade, intermediate‐grade, and high‐grade tumors based on morphologic criteria and the proliferation rate. Most studies have been conducted in patients with well differentiated (low‐grade to intermediate‐grade) neuroendocrine tumors. Data are substantially scarcer on poorly differentiated, high‐grade neuroendocrine carcinoma (NEC), which includes the entities of small cell carcinoma and large cell NEC. A literature search of GEP‐NEC was performed. Long‐term survival was poor even among patients who presented with localized disease. Several studies highlighted heterogeneity within the high‐grade NEC category and a need for the further identification of discreet prognostic and predictive groups. Tumors with a Ki‐67 proliferation index <55% were less responsive to platinum‐based chemotherapy, and patients with such tumors or with well differentiated morphology had better survival than patients who had tumors with poorly differentiated morphology or a higher Ki‐67 index. Treatment options beyond platinum‐based chemotherapy are emerging. A revision of the World Health Organization high‐grade NEC classification seems to be necessary based on recent data. Platinum‐based chemotherapy may not be the optimal treatment for patients who have GEP‐NEC with a moderately high proliferation rate. Adequate diagnostic and prognostic stratifications constitute the basis for future progress. Cancer 2014;120:2814–2823. © 2014 American Cancer Society. High‐grade gastroenteropancreatic neuroendocrine carcinoma is a very aggressive disease, and its diagnosis and treatment remain huge challenges for clinicians. Recent results question the current World Health Organization classification, indicating that current treatment strategies are not optimal and likely will change in clinical practice.