Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable attention over recent years. Significant beneficial effects of DHEA replacement have been reported in patients representing the pathophysiological model of complete DHEA deficiency, in other words, adrenal insufficiency (AI). This includes effects on well-being, energy levels, mood, and libido, which is usually impaired in AI, particularly in female patients. DHEA exerts its action mainly indirectly via downstream metabolism to sex steroids, and conversion to active androgens is likely to play a major role. In addition, DHEA has well-described neurosteroidal properties, and by exerting anti-gamma aminobutyric acid(GABA)ergic action it may have antidepressive potential. Other patient groups that may benefit from DHEA replacement are patients receiving chronic exogenous glucocorticoid treatment, which invariably leads to persistent suppression of DHEA production. In patients with systemic lupus erythematosus, DHEA has been shown to reduce disease activity and has a glucocorticoid-sparing effect. However, caution is required regarding DHEA treatment in individuals with only a relative decline in circulating DHEA levels. This particularly includes the physiological decline of DHEA and its sulfate ester observed with aging. Even the elderly maintain circulating levels of DHEA that are orders of magnitude higher than what is observed in AI. Even physiological menopause does not necessarily lead to a decrease in circulating androgens while estrogen production invariably ceases. Current evidence from randomized, controlled trials in healthy elderly persons including several cohorts of postmenopausal women does not justify the use of DHEA. However, DHEA may be a suitable option for androgen replacement in women with established androgen deficiency, for example, bilateral oophorectomy and premature menopause.