Fever of unknown origin (FUO) in adults is defined as a temperature higher than 38.3 degrees C (100.9 degrees F) that lasts for more than three weeks with no obvious source despite appropriate investigation. The four categories of potential etiology of FUO are classic, nosocomial, immune deficient, and human immunodeficiency virus-related. The four subgroups of the differential diagnosis of FUO are infections, malignancies, autoimmune conditions, and miscellaneous. A thorough history, physical examination, and standard laboratory testing remain the basis of the initial evaluation of the patient with FUO. Newer diagnostic modalities, including updated serology, viral cultures, computed tomography, and magnetic resonance imaging, have important roles in the assessment of these patients.