Fever of undetermined origin (FUO) is a challenging entity with a striking presence in hospitals around the world. It is defined as temperature ≥ 37.8 ° C on several occasions, lasting ≥ three weeks, in the absence of diagnosis after three days of hospital investigation or 3 outpatient visits. The main etiologies are infectious, neoplastic, and non-infectious inflammatory diseases. The diagnosis is based on the detailed clinical history and physical examination of these patients, in order to direct the specific complementary tests to be performed in each case. The initial diagnostic approach of the FUO patient should include non-specific complementary exams. Empirical therapy is not recommended (with few exceptions) in patients with prolonged fever, as it may disguise and delay the diagnosis and conduct to treat the specific etiology. The prognosis encompasses mortality of 12-35%, varying according to the baseline etiology.