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Fevers of unknown origin remain one of the most difficult diagnostic challenges in medicine. Because fever of unknown origin may be caused by over 200 malignant/neoplastic, infectious, rheumatic/inflammatory, and miscellaneous disorders, clinicians often order non-clue-based imaging and specific testing early in the fever of unknown origin work-up, which may be inefficient/misleading. Unlike most other fever-of-unknown-origin reviews, this article presents a clinical approach. Characteristic history and physical examination findings together with key nonspecific test abnormalities are the basis for a focused clue-directed fever of unknown origin work-up.