DHEA is the major circulating steroid in human blood and it is a central intermediate in the metabolic pathway of sex steroid hormone formation. Although the specific effect of DHEA is still unclear it was demonstrated that DHEA modulates several physiologic processes including metabolism and cardiovascular function. Furthermore, a profound immunomodulatory effect of DHEA was reported. Several data demonstrate the beneficial effect of DHEA in situations of critical illness including trauma hemorrhage and sepsis. Accordingly DHEA improved the survival rate and physiological situation in several animal models of trauma hemorrhage and systemic inflammation. This effect was paralleled by profound changes of immunologic parameters, organ function, and heat shock protein production. Therefore, it was claimed that DHEA may be a new alternative/additive in the treatment of trauma and sepsis. In line, DHEA is a frequently used drug in the field of anti-aging medicine, it is an over-the-counter drug in several countries, and it was reported that DHEA medication is free of major side effects. Therefore, DHEA could easily be used in a clinical trial investigating its effects in critical ill patients. This article reviews the reported effects of DHEA on the base of the literature with the specific focus on trauma and sepsis/ critical illness including its clinical perspectives.