Cushing’s syndrome is associated with significant morbidity and mortality and should be considered in specific clinical circumstances, including patients who accrue suggestive symptoms and signs, have features inappropriate for their age, or have incidental adrenal or pituitary lesions. Exogenous glucocorticoid use should always be thoroughly ascertained, as this is the most common cause of Cushing’s syndrome in the general population. If possible, testing for Cushing’s syndrome should be deferred to the outpatient setting, with the exception of acutely ill patients whose presenting symptoms could be directly related to hypercortisolism. Diagnostic testing should first document the presence of pathologic hypercortisolism, and should then determine whether the source is ACTH-dependent (pituitary or ectopic causes) or ACTH-independent (adrenal causes). Tumor-directed surgery should be considered as first-line treatment; pharmacotherapy and radiotherapy are also useful in specific situations. Bilateral adrenalectomy is generally used as a last resort, but can be lifesaving in acutely ill patients, whose hypercortisolism is of unclear source or those with unresectable tumors and inadequate response to medical therapy. Cushing’s syndrome in pregnancy is associated with significant maternal and fetal morbidity and mortality, wherein its diagnosis and management can be challenging.