Primary adrenal insufficiency is treated with glucocorticoid and mineralocorticoid replacement therapy. Recent data revealed that health-related quality of life in adrenal insufficiency is impaired in many patients and that patients with adrenal insufficiency are also threatened by an increased mortality and morbidity. This may be caused by inadequate glucocortiocid therapy and adrenal crisis. Therefore, the optimization of hormone replacement therapy remains one of the most challenging tasks in endocrinology because it is largely based on clinical grounds because of the lack of objective assessment tools. This article provides answers to the important daily clinical questions, such as correct dose finding, dose adaptation in special situations, e g, pregnancy, improvement of quality of life and measures for protection from adrenal crisis. Other important aspects discussed are side effects of glucocortiocid replacement therapy and interactions with other drugs.