Fever is a common problem for which patients seek medical advice. Fortunately, in most cases, fever is self-limiting or the etiology of fever is promptly established. Sustained, unexplained fever despite a comprehensive work up is recognized as fever of unknown origin (FUO), which frequently poses a clinical challenge. For a methodical approach, FUO is recently categorized into classic FUO, nosocomial FUO, neutropenic FUO and HIV-associated FUO based on the clinical setting and patient's underlying immune status. This review focuses on the key factors of classic FUO. The etiologic clues obtainable from the history, bedside physical examination findings and pertinent laboratory tests are discussed. Also, FUO in older patients and tuberculosis as a cause of FUO are briefly discussed.