The stress response to acute disease is characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenal system, increased serum cortisol levels, increased percentage of its free fraction and increased nuclear translocation of the glucocorticoid-receptor complex, even though many pathways may be inhibited by poorly understood mechanisms. There is no consensus about the cutoff point of serum cortisol levels for defining adrenal insufficiency. Furthermore, recent data point to the participation of tissue resistance to glucocorticoids in acute systemic inflammatory processes. In this review, we evaluate the evidence on HPA axis dysfunction during critical illness, particularly its action on the inflammatory response, during acute severe injury and some pitfalls surrounding the issue. Critical illness-related corticosteroid insufficiency was defined as a dynamic condition characterized by inappropriate cellular activity of corticosteroids for the severity of the disease, manifested by persistently elevated proinflammatory mediators. There is no consensus regarding the diagnostic criteria and treatment indications of this syndrome. Therefore, the benefits of administering corticosteroids to critically ill patients depend on improvements in our knowledge about the possible disruption of its fragile signalling structure in the short and long term.