This article reviews the chronic fatigue syndrome (CFS), a disorder whose etiology is unknown. The diagnostic criteria proposed in 1994 by the CDC and the International Chronic Fatigue Syndrome Study Group are introduced. In contrast to widespread belief, there are no laboratory tests available to underpin the diagnosis of CFS; the diagnosis is made solely on the basis of clinical criteria. In the differential diagnosis, the exclusion of other conditions that can cause chronic fatigue, such as neuropsychiatric or sleep disorders, is of critical importance. In this context, the question as to whether CFS is a clinical entity that can be differentiated from psychiatric diagnoses, such as depression, somatoform disorder, or neurasthenia, is discussed. At the moment, there is no specific therapy for CFS. Therefore, therapeutic approaches are limited to symptomatic management of the concomitant sleep disturbances, pain, or psychiatric symptoms, such as depression. Patients may benefit from cognitive behavioral therapy, as this may help then to identify and exclude factors contributing to and maintaining chronic fatigue. An integrated medical and psychological approach should be adopted, with the aim of preventing significant secondary negative results of the illness, such as interpersonal conflicts or chronic disability.