Fever of Unknown Origin, or FUO, is a challenging condition for patients and clinicians. In up to 50% of cases, no diagnosis is established. Patient workup begins with comprehensive history, physical examination and laboratory tests. Radionuclide imaging has been a second-line procedure. Gallium-67 citrate, which accumulates in infection, inflammation, and tumor, was for many years, the radionuclide test of choice in the workup of FUO. The 24-72 hours between injection and imaging, relatively high radiation dose to patients, and suboptimal image quality are significant disadvantages; imaging results are variable. Although labeled leukocyte imaging accurately localizes infection, infections cause only about 20%-40% of all FUO’s. In most cases, this test is not helpful in identifying the source of the fever. Fluorine-18-fluorodeoxyglucose (FDG) uptake is related to cellular glucose metabolism. Increased FDG uptake is present in numerous hypermetabolic conditions, including tumor, infection, and noninfectious inflammation. FDG positron emission tomography (PET) and PET/computed tomography (CT) have rapidly assumed an increasingly important role in the diagnostic workup of patients with FUO. FDG is especially useful for localizing lesions and areas of interest for further evaluation. In contrast to gallium and labeled leukocyte imaging, FDG contributes useful information in children with FUO. Initially utilized as a second-line diagnostic tool in patients with FUO, recent data indicate that FDG contributes more diagnostically useful information than anatomic imaging like ultrasound and CT, which leads to earlier institution of appropriate therapy. These findings suggest that FDG imaging should be performed earlier, rather than later, in the diagnostic evaluation of the patient with FUO.