Fatigue, pain, and emotional upset remain the most common problems affecting humanity and for which we still know so very little. Chronic fatigue syndrome is most likely a number of as yet unproven various undifferentiated illnesses that are exceedingly difficult to distinguish from depression. There probably is a subset of patients with CFS who do have true immune dysfunction and persistent viral infection, and this particular group of patients should be further investigated. This group is the minority of patients who present with chronic fatigue. Although chronic fatigue syndrome may be the result of an organic illness in psychologically susceptible individuals, it remains most important to assess underlying psychologic factors that then need to be addressed. These factors may very likely have a profound effect on immune function, but more research is needed in this area. The diagnostic evaluation of patients with chronic fatigue syndrome should initially focus on causes for fatigue other than Epstein-Barr viral infection. Significant underlying medical conditions should be ruled out, and extensive inquiry into symptoms suggestive of depression and anxiety should be aggressively pursued. Treatment should include psychiatric support and counseling, good nutrition, adequate rest, and a gradual increase in activity. Anti-inflammatory agents and serotonin-replenishing antidepressants are helpful when muscle pain and tenderness are a major part of the patient's symptoms. Psychoactive drugs are useful when indicated. Low doses of antidepressants such as doxepin (10-25 mg at night) are generally well tolerated and have shown efficacy in numerous patients, although there are no reports of controlled trials.