The many unique features of glucocorticoids makes therapy with these steroids challenging. The anti-inflammatory potency, relative mineralocorticoid activity, plasma half-life, and route of administration of the synthetic cortisol preparations are compared. Because they produce profound anti-inflammatory and immunosuppressive effects, exogenously administered glucocorticoids are effective therapy for a variety of diseases and conditions. The appropriate dosing regimen is an adequate dose administered for a sufficient period to precipitate an acceptable response. It is impossible to predict the regimen that will suppress the hypothalamic-pituitary-adrenocortical (HPA) axis and thereby increase the risk of developing adrenal insufficiency during periods of stress. Until recovery of the axis is complete, patients require daily physiologic replacement doses; high-dose supplemental therapy may be required during a major illness or surgery. Once there are signs of improvement, the dosing regimen should be adjusted to a single morning dose, then to an alternate-day regimen, and, as soon as possible, the steroid should be discontinued. This tapering process maintains disease suppression while minimizing toxicity; however, it is often complicated by exacerbation of the disease and withdrawal symptoms. Potential complications associated with glucocorticoid therapy are numerous, involve all organ systems, and are potentially more devastating than the HPA axis suppression.