Although fever of unknown origin (FUO) was first defined in 1961, it remains a diagnostic challenge. The revised 1991 definition categorized FUO into classic FUO, nosocomial FUO, neutropenic FUO, and human immunodeficiency virus-related FUO, each requiring at least three outpatient visits or 3 days of in-hospital stay. The causes of classic FUO differ greatly geographically and temporally, and are divided into infections, noninfectious inflammatory diseases, neoplasms, and miscellaneous diseases. A systematic, comprehensive and rational approach is required for appropriate diagnosis. A medical history and physical examination are very important; they may reveal diagnostic clues. Here, we review the literature on the causes and diagnostic approaches of classical FUO. (Korean J Med 2021;96:101-109)