Homeostasis is a fundamental physiological principle that ensures equilibrium, stability and safety of the organism in a continuously changing and potentially life-threatening environment. This article introduces a new theory of the aetiology of ME/CFS that hypothesises that ME/CFS is caused by a breakdown of homeostasis that produces an aberrant state of disequilibrium with endocrinological and immunological changes. The current hypothesis is that ME/CFS involves a changed set point such that homeostasis persistently pushes the organism towards a pathological dysfunctional state because the disequilibrium fails to reset. To use an analogy of a thermostat, if the ‘off switch’ of a thermostat stops working, the house would become warmer and warmer without limit. Here I summarise the evidence in support of the theory. Clinical trials to investigate the role of suggested biological mediators such as thyrotropin-releasing hormone in ME/CFS would appear to be helpful.