The contribution of adrenal insufficiency (AI) to the morbidity of critically ill patients is currently under renewed scrutiny. Activation of the hypothalamic–pituitary–adrenal (HPA) axis is an integral part of the organism’s response to stress and so a thorough understanding of the normal functioning of the HPA axis and potential pathophysiological changes is essential. Yet despite over 50 years of research, the nature and significance of the changes that occur in the system and the response of the adrenal gland to critical illness is still the subject of debate. The definitions of the syndromes “relative adrenal insufficiency” (RAI) and “critical illness related corticosteroid insufficiency” (CIRCI) have been the subject of intense controversy. In this chapter, we review the adrenocortical physiology and the feedback loops, discuss the clinical features of and the optimal methods for diagnosing adrenal insufficiency, and discuss possible pathways of future research.