BACKGROUND–The neurologist is often asked to evaluate patients with a chief complaint of fatigue. Many neurologists do not believe in the pathologically based disease known as chronic fatigue syndrome (CFS), yet as a group, neurologists are well suited to guide the diagnostic work up of such patients to pinpoint treatable disorders in the realm of neurology, general medicine, and psychiatry.REVIEW SUMMARY–Every patient should be carefully evaluated for certain medical, psychiatric, and neurologic disease that can cause fatigue as the most prominent symptom. This is most pressing because new work in virology, immunology, and imaging holds promise but still does not provide any diagnostic test or a mechanism for the production of these symptoms. Only a few treatments meet with even modest success in CFS. The goal of this paper is to provide the clinical neurologist with a framework for the investigation and management of this challenging group of patients.CONCLUSION–Neurologists are typically also trained in psychiatry and general medicine, and this is a strong position to evaluate the patient with fatigue. Because no presently available test can make the diagnosis of CFS, the assessment is vital to seek out more treatable illnesses.