Although grouped under the same name, neuroendocrine tumors comprise a heterogeneous family of neoplasms with a wide range of clinical and biological behaviors and responses to different treatment options. Most of the tumors derived from enterochromaffin cells are indolent or at least not as aggressive as epithelial tumors. However, a small percentage of these tumors have a poor prognosis and highly aggressive histology that results in a very short overall survival and scarce treatment options compared with well and moderately differentiated tumors. Patients with poorly differentiated neuroendocrine carcinomas barely exceed 6-8 months of survival. This particular poor risk subgroup of neuroendocrine tumors remains an unmet medical need and becomes a challenge in the daily clinical practice. A deeper knowledge of the biology and novel targeted agents might allow for future clinical development of novel agents in this setting. In this review we summarize the current background behind the management of poorly differentiated neuroendocrine carcinomas in daily clinical practice.