Replacement therapy in adrenal insufficiency comprises treatment with glucocorticoids, mineralocorticoids and adrenal androgen precursors. Initiation of hormone replacement therapy in newly diagnosed adrenal insufficiency leads to rapid and impressive improvements. However, despite the use of established replacement concepts, well-being is often not fully restored in patients with adrenal insufficiency, and life expectancy may even be reduced. This has led to a reconsideration of current replacement strategies. Several studies demonstrate that addition of dehydroepiandrosterone (DHEA) to the treatment regimen may lead to further improvement of general well-being and also sexual function. However, long-term trials with DHEA are still lacking, and DHEA alone is not able to restore subjective health status to normal. Further innovations comprise the development of delayed-release glucocorticoid preparations that better allow mimicking of circadian cortisol secretion and may have the potential to significantly improve the treatment of patients with adrenal insufficiency. However, future studies have to prove the clinical importance of physiological cortisol day profiles. To date, no relevant risk factors for susceptibility to adrenal crisis are known, and patient education is key for a successful prevention strategy. In our experience the well-educated patient often guides the physician not familiar with this disease.