Extrapulmonary small cell carcinoma (EPSCC) is usually treated similarly to small cell lung cancer. Differences in aetiology, clinical course, frequency of brain metastases, and survival, however, warrant a differential therapeutic approach. In this review, we focus on the treatment of the most predominant sites of origin of EPSCC; the gastrointestinal tract, the genitourinary tract, the head and neck region, and small cell carcinoma of unknown primary. Furthermore we review the available data concerning the controversial issue of prophylactic cranial irradiation (PCI) after optimal treatment of EPSCC. We found in the literature a significant lower incidence of brain metastases in EPSCC as compared to pulmonary small cell carcinoma when PCI is omitted and therefore we do not recommend PCI. An exception is EPSCC originating from the head and neck region which is associated with a higher incidence of brain metastasis, justifying addition of PCI.