Fever of undetermined origin (FUO) is a challenging entity with a striking presence in hospitals around the world and can be associated with a myriad of differential diagnoses. It is defined as axillary temperature ≥ 37.8 ° C on several occasions, lasting ≥ three weeks, in the absence of diagnosis after three days of hospital investigation or three outpatient visits. The main etiologies are: infectious, neoplastic, and rheumatic. 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. 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 underlying etiology. In this sense, the objective of this study is to review the main topics about fever of undetermined origin, bringing historical and scientific aspects, national and international.