ACTH-independent cortisol production in adrenal Cushing's syndrome previously was believed to be autonomous. Recent work by our group and others has shown that, in certain patients with bilateral macronodular adrenal hyperplasia or unilateral adrenocortical tumor, cortisol production may be under the control of abnormal or ectopic hormone receptors. The aberrant regulation of cortisol production by GIP, vasopressin, β-adrenergic agonists, hCG/LH, or serotonin illustrates this concept. The identification of an abnormal adrenal receptor offers the possibility of new pharmacological approaches to control hypercortisolism by suppressing the endogenous ligands or by blocking the abnormal receptor with specific antagonists. This review will describe the in vivo investigation protocols utilized by our group to identify the presence of abnormal hormone receptors in primary adrenal Cushing's syndrome.