The classical model of the vital increase in systemic glucocorticoid availability in response to sepsis- and hyperinflammation-induced critical illness is one of an activated hypothalamus-pituitary-adrenocortical axis. However, research performed in the last decade has challenged this rather simple model and has unveiled a more complex, time-dependent set of responses. ACTH-driven cortisol production is only briefly increased, rapidly followed by orchestrated peripheral adaptations that maintain increased cortisol availability for target tissues without continued need for increased cortisol production and by changes at the target tissues that guide and titrate cortisol action matched to tissue-specific needs. One can speculate that these acute changes are adaptive and beneficial for the host. Treatment with stress-doses of hydrocortisone has pharmacological effects but has also shown to negatively interfere with these adaptive changes. The new insights also suggest that prolonged critically ill patients, treated in the ICU for several weeks, may develop central adrenal insufficiency, although it remains unclear how to best diagnose and treat this condition.