The maintenance of life depends on the capacity of the organism to sustain its equilibrium via allostasis'-the ability to achieve stability through change. Life-threatening disease induces acute adaptive responses specific to the stimulus and generalized responses when the disturbances are prolonged. These changes are associated with increased activity of the hypothalamic-pituitary-adrenal axis and may have survival value in preparing the body for fight or flight'. There is a shift towards an increase in glucocorticoid production and away from mineralocorticoid and androgen production, as well as an increase in the biological effects of glucocorticoids through an increased cortisol free fraction and an increased glucocorticoid receptor sensitivity. During the prolonged phase, there is a dissociation between high plasma cortisol and low adrenocorticotropin hormone levels, suggesting non-adrenocorticotropin hormone-mediated mechanisms for the regulation of the adrenal cortex. This hypercortisolism is in contrast to the very low dehydroepiandrosterone sulphate level, indicating an imbalance between the immunostimulatory and immunosuppressive adrenocortical hormones. The question is whether the total serum cortisol concentration represents sufficient glucocorticoid biological activity during the prolonged phase of critical illness. Copyright 2001 Harcourt Publishers Ltd.