Multiple factors may account for the chronic toxicity of synthetic glucocorticoids (GCs), which are (too) widely prescribed in clinical practice. The relative potency of the GCs used, daily dose administered, duration of treatment, route and time of administration, as well as individual factors like age, genetic factors, or significant co-morbidity, such as renal or hepatic failure, determine the delay in the occurrence of potentially serious complications, including the suppression of the corticotropic axis. The concomitant use of drugs affecting the metabolism and/or the action of these glucocorticoids must also be considered. While the selected treatment strategy should take into account all these factors, it must also consider the desired effects and proofs of efficacy. Whenever possible, short-term treatment or non-systemic administration of glucocorticoids should be preferred. Iatrogenic Cushing's syndrome is characterized by specific complications, including posterior subcapsular cataract, benign intracranial hypertension, osteonecrosis of the femoral and humeral heads, tendon ruptures, pancreatitis or psychotic crisis. Suppression of the hypothalamus-pituitary-adrenal (HPA) axis can be assumed in patients receiving over 16mg of methylprednisolone per day (or equivalent dose) for at least 6 weeks and in those exhibiting clinical Cushing’s syndrome. On the contrary, this condition is rather unlikely in patients receiving nonparenteral corticosteroids for less than 3 weeks. In other situations, adrenal function must be assessed before considering glucocorticoid withdrawal. This comprises the measurement of morning plasma cortisol levels, in addition to a short corticotropin (ACTH) stimulation test. If the results confirm either complete or partial suppression of the HPA axis, treatment with hydrocortisone (20mg/day in the morning) should be administered until recovery of adrenocortical function.