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Simple Summary: Extra-pulmonary poorly differentiated neuroendocrine carcinoma is a rare tumour type with a limited evidence base for its treatment. Recent work has helped to clarify the optimum first-line chemotherapy regimen. However, in the second-line setting, data remain sparse. A more personalised approach is warranted, given the heterogeneity of this disease, and emerging translational approaches focused on mouse models, organoids, and comprehensive genomic profiling may guide future trial design. Extra-pulmonary poorly differentiated neuroendocrine carcinoma is rare, and evidence for treatment has been limited. In this article, the evidence behind the cytotoxic chemotherapy choices used for metastatic or unresectable EP-PD-NEC is reviewed. In the first-line setting, etoposide and platinum chemotherapy or irinotecan and platinum have been demonstrated to be equivalent in a large phase III trial. Questions remain regarding the optimal number of cycles, mode of delivery, and the precise definition of platinum resistance in this setting. In the second-line setting, FOLFIRI has emerged as an option, with randomized phase 2 trials demonstrating modest, but significant, response rates. Beyond this, data are extremely limited, and several regimens have been used. Heterogeneity in biological behaviour is a major barrier to optimal EP-PD-NEC management. Available data support the potential role of the Ki-67 index as a predictive biomarker for chemotherapy response. A more personalised approach to management in future studies will be essential, and comprehensive multi-omic approaches are required to understand tumour somatic genetic changes in relation to their effects on the surrounding microenvironment. [ABSTRACT FROM AUTHOR]