Many studies of patients with long-standing chronic fatigue syndrome (CFS) have found alterations to the hypothalamo-pituitary-adrenal (HPA) axis, including mild hypocortisolism, heightened negative feedback and blunted responses to challenge. However, recent prospective studies of high-risk cohorts suggest that there are no HPA axis changes present during the early stages of the genesis of fatiguing illnesses. Moreover, HPA axis changes can be reversed by modifying behavioural features of the illness, such as inactivity, deconditioning and sleep disturbance. Nevertheless, raising levels of cortisol pharmacologically can temporarily alleviate symptoms of fatigue. This article presents the case that there is no specific change to the HPA axis in CFS and that the observed changes are of multifactorial aetiology, with some factors occurring as a consequence of the illness. Nevertheless, the HPA axis might play a role in exacerbating or perpetuating symptoms late on in the course of the illness.