Fever of unknown origin (FUO) is a diagnosis that describes a prolonged febrile illness without an established cause, despite investigations. From the first definition of the medical condition (given by Petersdorf and Beeson in 1961) the diagnostic criteria have changed over time, intending to improve the management and outcome of these patients. The main causes of FUO fall into 4 categories: infectious, non-infectious (inflammatory), neoplastic and diverse causes. The etiology of FUO has changed over time, due to ever-changing disease patterns and the development of diagnostic techniques. A significant percentage of patients with FUO remain without an etiologic diagnosis, despite advanced diagnostic tests. Gathering potentially diagnostic clues through history, physical examination and nonspecific key paraclinical abnormalities is the basis for the diagnosis of FUO.