Fever of unknown origin represents a clinical syndrome characterized by a fever of over 38.3 °C documented on several occasions during a period of at least 3 weeks, etiology of which remains unexplained after obtaining a detailed history, conducting a thorough physical exam, and an array of basic laboratory tests and diagnostic imaging. Most cases of this syndrome are caused by infections, non-infectious inflammatory diseases, and neoplasms. In addition, drug fevers and internal medicine diseases should be included in the differential diagnostic work-up in all patients. This article presents five case reports of fever of unknown origin managed at an outpatient clinic of a tertiary care center for infectious diseases. This case series emphasizes the need for a consistent, broad and interdisciplinary diagnostic work-up. In addition, we present a review of the etiology and clinical management of fever of unknown origin.