Prolonged fever presents a challenge for the patient and the physician. Fever with a temperature higher than 38.3 degrees C on several occasions that lasts for at least 3 weeks and lacks a clear diagnosis after 1 week of study in the hospital is called a fever of unknown origin (FUO). More than 200 diseases can cause FUO, and the information gathered from history taking, physical examination, laboratory and imaging studies should be evaluated with care. History taking and physical examination may provide some localizing signs and symptoms pointing toward a diagnosis. Infection, cancers, noninfectious inflammatory diseases and some miscellaneous diseases are the main etiologies, and some patients remain undiagnosed despite investigations. Tuberculosis, lymphoma and adult-onset Still's disease are the main diseases. Fluorodeoxyglucose PET is a promising imaging modality in FUO. Establishing a uniform algorithm for FUO management is difficult. Every patient should be carefully evaluated individually considering the previous FUO management experience.