Fever of unknown origin (FUO) has fascinated and perplexed clinicians for over a century. No published guidelines exist on the approach to FUO, and studies have demonstrated that a diagnosis is never established in up to 30% of cases. A comprehensive history and physical examination are the keys to establishing a diagnosis in patient with FUO. This article provides a systematic approach to the diagnosis of FUO by delineating the most important elements of a comprehensive history and physical examination.