Chronic fatigue syndrome (CFS) is a term applied to individuals who report severe chronic fatigue out of proportion to their efforts, but the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Fourth and Fifth Editions, are clear that no ratable impairment is linked to CFS. Chronic fatigue is not synonymous with CFS; only a small fraction of persons who present with chronic fatigue symptoms meet the criteria for CFS; and CFS, like fibromyalgia and multiple chemical sensitivity, is poorly understood. CFS may be associated with disability but primarily is based on psychological rather than physical symptoms. No tests confirm the diagnosis of CFS, and routine laboratory testing is reserved for excluding other medical conditions. CFS is an illness without a disease and often is characterized by illness behavior expressed as somatization. To date, no convincing evidence supports the notion that CFS is an infectious, neuroendocrine, or immunologic disorder. Thus, sophisticated behavioral assessment is critical and may include a fatigue rating scale, a depression scale, and psychological and personality inventories. No specific treatment has been recommended for CFS treatment, but cognitive and behavioral interventions may be useful to address psychological symptoms; medication is reserved for specific symptoms indicative of depression or anxiety.