Chronic fatigue syndrome (CFS) is an illness characterised by incapacitating fatigue and a pattern of somatic complaints without known cause. It is a controversial illness in that symptoms are subjective and overlap with symptoms of primary emotional disturbance.The natural history of this illness is often characterised by spontaneous improvement, and a significant placebo response is frequently present. Therefore, results from poorly controlled trials may be misleading. Few adequate treatment trials have been done in patients with CFS, due to difficulties in case definition and the lack of definitive biological markers. However, numerous treatment regimens have been proposed over the last 30 years, the majority emphasising either psychotropic, immunological or antimicrobial therapy. While no single agent has been curative, benefit has been claimed for many agents. These include tricyclic antidepressants, the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors fluoxetine and sertraline, amfebutamone (bupropion), immunoglobulin G, mismatched double-stranded RNA [Poly(I):Poly(C12U); ‘ampligen’] and essential fatty acids.