Fever of unknow origin (FUO) is a difficult problem that internal medicine physicians often encounter, with a variety of causes and different clinical manifestations, and it is not easy to confirm the diagnosis. Most patients with fever of unknow origin cannot be diagnosed in a timely manner, resulting in prolonged illness and great physical and mental pain, as well as great financial pressure. Once the cause of these diseases is clearly identified, treatment can be targeted to minimize the pain and medical costs of patients. With the development of social economy and the serious aging of the population, the elderly have become the main group of patients. As early as 1961, Petersdorf and Beeson first proposed the definition of “fever of unknown origin” (FUO) through a prospective study of 100 patients: a disease with recurrent fever over 38.3°C, lasting for more than 3 weeks, and not clearly diagnosed after 1 week of hospitalization. Due to advances in medical technology and diagnostic procedures, many patients can be treated and examined on an outpatient basis, so in 1992 Petersdorf proposed amending the phrase “unable to make a definitive diagnosis after 1 week of hospitalization” to “unable to make a definitive diagnosis after 1 week of detailed examination. “In 1999, the National Symposium on Febrile Diseases defined unexplained fever as a fever lasting for more than 3 weeks with a temperature ≥38.3°C, which could not be diagnosed after detailed history, physical examination and routine laboratory tests. The advantages of this concept mainly include: (1) eliminating certain viral infections that can be diagnosed; (2) eliminating short-term fevers with clearer etiology and easier diagnosis; (3) eliminating unexplained fevers that can resolve spontaneously within a short period of time; and (4) eliminating functional fevers that manifest as hypothermia. Therefore, the concept of fever of unknown origin (FUO) actually refers to that part of the disease group that is truly and more difficult to diagnose. Fever is the result of both pyrogenic and non-pyrogenic factors. Therefore, in the case of fever caused by physical or chemical factors acting directly on the thermoregulatory center, the source of fever needs to be actively sought. Thermogenic sources are classified as exogenous or endogenous. Exogenous pyrogenic sources are substances that activate pyrogenic cells to produce and release pyrogenic cytokines, also known as fever activators (EP inducers). They are: (1) microbial fever activators: exotoxins and peptidoglycans of gram-positive bacteria, peptidoglycans and lipopolysaccharides of gram-negative bacteria (also called endotoxin ET), viruses and fungi; (2) non-microbial fever activators: mainly antigen-antibody complexes activate EP cells to produce and release EP that acts on thermoregulatory centers, causing the release of febrile mediators and subsequently changing the thermoregulatory point. Endogenous pyrogen is a large group of small molecule proteins or peptides that are synthesized and released by immune cells and some non-immune cells, and have intercellular messaging and immunomodulatory effects. They mainly include interleukin-1 family (IL-1) and IL-1 receptor antagonist protein (IL- 1ra), tumor necrosis factor-α (TNF-α), interleukin-6 (IL- 6), interferon (IFN-α) and other inflammatory factors involved in the febrile response. In patients with fever of unknown origin occurring for the first time, treatment may be delayed due to improper treatment and management and misjudgment of the underlying infection (e.g., osteomyelitis, spondylitis, endocarditis, etc.). There is also the possibility of an immune reaction to antigens, crystalline substances, and necrotic substances (e.g., allergic pneumonia). Drug fever is caused by non-rational drug use. Some self-remitting and recurrent unexplained fevers (e.g., Still’s disease) are also an important cause. It has been reported that 18-42% of patients with recurrent fever have unexplained fever, and a significant proportion have a long history of the disease, even up to several years or more. Aduan RP reported that of 347 patients with unexplained fever for more than 6 months at the National Institutes of Health, only 54% had a definite cause. 61% of the 199 patients with unexplained fever followed up for at least 5 years by Daniel C et al. were still undiagnosed. In recent years, with the rapid development of medical science, more and more attention has been paid to unexplained fever, and some cases of unexplained fever that could not be clearly diagnosed in the past are now being diagnosed and treated promptly. In recent years, there have been many studies on the etiology of unexplained fever at home and abroad, and there are many causes, and it has been reported that there are more than 200 causes of unexplained fever. The disease spectrum varies from time to time and from region to region, and the etiological composition of special populations also has its own specificity. Infectious diseases have long been the most common cause of FUO, but in recent years, the proportion of infectious diseases in the cause of FUO has decreased, especially in economically developed regions of North America and Northwest Europe, where the proportion has dropped to about 30%. A Mexican study showed that the infectious causes of FUO have been decreasing every decade for the past 40 years, while the proportion of immune diseases and tumors has been gradually increasing. However, infectious diseases are still the most common cause of FUO in developing countries, including China, and about 40-50% of FUO is caused by these diseases. In the analysis of the causes of FUO in Concord Hospital from 2000 to 2003, it was reported that infectious diseases still took the first place, accounting for about 43.6%. The proportion of connective tissue-vascular diseases in the etiology of FUO has increased in recent years, accounting for about 20-30%, and the common ones include rheumatoid arthritis, systemic lupus erythematosus, Still’s disease, vasculitis, polymyositis, drug fever, and mixed connective tissue disease. Due to the improvement of living standards and the development of laboratory diagnostic techniques, the proportion of rheumatic fever and systemic lupus erythematosus, especially rheumatic fever, has decreased, but the trend of aging of society has led to an increasing incidence of rheumatic polymyalgia, primary small vessel vasculitis, temporal arteritis and other previously rare diseases. With the development of CT, MRI and other imaging technologies, the proportion of neoplastic diseases has decreased, accounting for about 20%, with lymphoma accounting for the highest proportion. China has entered an aging society. According to the data of the sixth national census released in 2011, 13.26% (178 million) of the population were aged 60 and above, up 2.93 percentage points from the 2000 census, of which 8.87% (119 million) were aged 65 and above, up 1.91 percentage points from the 2000 census. The physiological decline of the elderly is accompanied by a decline in the immunity of the body, and an increase in underlying diseases, making them the main group of people with the disease. FUO in the elderly is more difficult to diagnose and treat because of the atypical clinical symptoms and the long duration of the disease, high medical costs and high mortality rate. The results of foreign studies on the etiology of FUO in the elderly and non-elderly have shown that the etiological spectrum of FUO differs by age. Among the causes of FUO in the elderly, immune factors, malignancy, soft tissue inflammation, vasculitis, and osteomyelitis are common factors of FUO, and in developed countries, connective tissue disease is in the first place, and infectious causes have been reduced to the second or even third place of common FUO causes. Moreover, fungal or bacterial infections are also common causes of FUO in patients with combined diabetes.