Fever of unknown origin (FUO) refers to disorders that present with prolonged and perplexing fevers that are difficult to diagnose. This article presents a clinical overview of classic and current causes of FUOs, which may be due to infectious, rheumatic/inflammatory, neoplastic, or miscellaneous disorders. Comprehensive but nonfocused diagnostic testing is ineffective and should be avoided. The FUO workup should be directed by the key history, physical, and laboratory findings in clinical presentation. The clinical syndromic approach in the differential diagnosis of FUOs is emphasized, and the diagnostic importance and significance of fever patterns are discussed.