Chronic fatigue syndrome (CFS) is a prevalent condition affecting about one in 100 patients attending primary care. There is no diagnostic test, validated biomarker, clear pathophysiology or curative treatment. The core symptom of fatigue affects both physical and cognitive activities, and features a prolonged post-activity exacerbation triggered by tasks previously achieved without difficulty. Although several different diagnostic criteria are proposed, for clinical purposes only three elements are required: recognition of the typical fatigue; history and physical examination to exclude other medical or psychiatric conditions which may explain the symptoms; and a restricted set of laboratory investigations. Studies of the underlying pathophysiology clearly implicate a range of different acute infections as a trigger for onset in a significant minority of cases, but no other medical or psychological factor has been reproducibly implicated. There have been numerous small case–control studies seeking to identify the biological basis of the condition. These studies have largely resolved what the condition is not: ongoing infection, immunological disorder, endocrine disorder, primary sleep disorder, or simply attributable to a psychiatric condition. A growing body of evidence suggests CFS arises from functional (non-structural) changes in the brain, but of uncertain character and location. Further functional neuroimaging studies are needed. There is clear evidence for a genetic contribution to CFS from family and twin studies, suggesting that a large scale genome-wide association study is warranted. Despite the many unknowns in relation to CFS, there is significant room for improvement in provision of the diagnosis and supportive care. This may be facilitated via clinician education.