Within the past 5 years, F-18 fluorodeoxyglucose (FDG) PET/CT has become one of the more frequent imaging modalities in the management of patients with cancer of unknown primary origin. FDG PET/CT detects more sites of metastasis than other modalities, and in 20% to 40% of cases it discloses the site of the primary tumor. Its exact role is yet to be defined because of a lack of prospective clinical trials comparing the performance of PET/CT with conventional anatomic imaging modalities. This article reviews the available literature, attempts to place PET/CT using F-18-labeled FDG in clinical perspective and compares the combined modality with conventional anatomic imaging technologies.