Carcinoma of unknown primary (CUP) is defined as histologically proven metastatic disease that, after a complete diagnostic work-up, yields no primary detectable tumor. CUP is one of the ten most frequent cancers, with overall poor outcome. Detection of the unknown primary tumor is of crucial importance in this scenario, since it might help to select and offer definitive treatment, which, in turn, may improve patient prognosis. Additional diagnostic work-up, usually consisting of a combination of several radiological and endoscopic investigations and serum tumor marker studies, can be time consuming, expensive, and pose a significant burden to the patient. The final diagnostic yield of these tests is often limited. Combined positron emission tomography/computed tomography (PET/CT), using the radiotracer (18)F-fluoro-2-deoxyglucose (FDG), may be of great value in the management of patients with CUP for the detection of primary tumors. This chapter gives a brief introduction to the syndrome of CUP, followed by an outline of the rationale, use, and utility of FDG-PET/CT in CUP, and concludes with a discussion on the challenges and future directions in the diagnostic management of patients with CUP.