Adrenal insufficiency is caused by either primary adrenal failure, mostly due to autoimmune adrenalitis, or by hypothalamic-pituitary impairment of the corticotropic axis, predominantly by long-term pharmacodynamic glucocorticoid treatment or by pituitary tumour growth and related treatment. Despite optimized life-saving glucocorticoid and mineralocorticoid replacement therapy, health-related quality of life in adrenal insufficiency is more severely impaired than previously thought and patients with adrenal insufficiency are also threatened by an increased mortality. Optimizing hormone replacement remains one of the most challenging tasks in endocrinology. Monitoring of glucocorticoid replacement quality is hampered by lack of objective assessment tools and therefore largely based on clinical grounds. Thus, long-term management of patients with adrenal insufficiency remains a continuous challenge asking for the experienced specialist. However, diagnosis and management of suspected acute adrenal failure is an important task for all physicians. This review explains the rationale behind the current hormone replacement scheme, points to the deficits and hints at possible future therapies.