Fever of unknown origin is defined as a clinically documented temperature of 101°F or higher on several occasions, coupled with an unrevealing diagnostic workup. The differential diagnosis is broad but is typically categorized as infection, malignancy, noninfectious inflammatory disease, or miscellaneous. Most cases in adults occur because of uncommon presentations of common diseases, and up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis. In the absence of localizing signs and symptoms, the workup should begin with a comprehensive history and physical examination to help narrow potential etiologies. Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis. If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Depending on clinical indications, this may include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy. Empiric antimicrobial therapy has not been shown to be effective in the treatment of fever of unknown origin and therefore should be avoided except in patients who are neutropenic, immunocompromised, or critically ill.