Abstract Harvey Cushing described the first case of Cushing’s syndrome with a severe phenotype in 1912. Since that time, investigation and management of Cushing’s syndrome has remained a significant clinical challenge and patients suspected of this diagnosis warrant referral to major centres. Endogenous Cushing’s syndrome is due the chronic, excessive, and inappropriate secretion of cortisol. When presentation is florid, diagnosis is usually straightforward, but in modern practice Cushing’s syndrome is frequently and increasingly considered in mild cases in the absence of the classical signs in the context of osteoporosis, diabetes, and hypertension, as well as in the context of gynaecological and psychiatric clinics. Achieving a diagnosis can be difficult. Appropriate management of Cushing’s syndrome is dependent on correctly identifying the cause of excess cortisol. Separating ACTH-independent causes (adrenal tumours) from ACTH-dependent causes (pituitary or ectopic secretion of ACTH) is usually simple. However, many ectopic sources are occult and the identification of the source of ACTH secretion may require meticulous and repeated investigations. In most circumstances the mainstay of therapy remains surgery to either an ACTH-secreting tumour or directly to the adrenal glands, but additional treatment with cortisol-lowering or opposing drugs and tumour-directed therapy is often needed.