Carcinomas of an unknown primary origin (CUP) account for 3-5% of all malignancies and are thus among the ten most-frequent cancers worldwide. Having a specific and unique phenotype of early and usually aggressive metastatic dissemination with no identifiable primary tumor, CUP are a challenge for physicians. The diagnostic workup of patients with CUP includes a careful clinical and extensive histopathological examination, as well as the use of imaging techniques. CUP can be divided into favorable and unfavorable subsets. Patients with unfavorable CUP subsets have a poor prognosis with a median survival of approximately 8 months; the optimal chemotherapy regimen for these patients remains to be determined. Although studies have focused on the introduction of new cytotoxic agents with broad-spectrum clinical activity (such as gemcitabine, irinotecan, and taxanes), no randomized trial has provided clear evidence of a survival benefit. Molecular targeted therapies that are approved for other solid tumors are now considered for the treatment of patients with CUP. Molecular diagnostic tools, such as DNA microarray analysis, could help in the search for 'lost' CUP origins. In this Review, we describe the clinical evaluation of patients with CUP, and discuss treatment strategies and outcomes of patients with various CUP subsets.