Etomidate blocks the cortisol synthesis by specifically inhibiting the activity of 11 beta-hydroxylase, resulting in a primary adrenal insufficiency. Therefore, a serum accumulation of 11 beta-deoxycortisol and a low secretion of serum cortisol must be required as diagnostic criteria to assign that adrenal impairment to the drug. These requirements have been rarely fulfilled in studies exploring the contribution of etomidate to the adrenal insufficiency despite numerous causes of adrenal derangement. In critically ill patients without sepsis, a single dose of etomidate results in a wide adrenal inhibition, reversible in 48 h after etomidate administration. Although there are still uncertainties as to whether etomidate directly affects mortality and morbidity, it seems preferable to avoid the use of etomidate in patients with severe sepsis and septic shock. In patients with severe traumatic brain injury, arterial hypotension is one of major factors of poor outcome and can be prevented with the use of etomidate for facilitating tracheal intubation. Substitutive opotherapy with low doses of hydrocortisone should be assessed after a single dose of etomidate for critically ill patients.