The initial description of GIP-dependent Cushing's syndrome suggested that abnormal or ectopic expression of adrenal receptors for various ligands may underlie other cases of ACTH-independent hypercortisolism. GIP-dependent Cushing's syndrome has been described in patients with unilateral adenomas or bilateral ACTH-independent macronodular adrenal hyperplasia (AIMAH) and results from the adrenal overexpression of non-mutated GIP receptor. In AIMAH, other patients were identified in whom regulation of cortisol production resulted from an abnormal adrenocortical response either to vasopressin, beta-adrenergic receptor agonists, hCG/LH, or serotonin 5-HT-4 receptor agonists. The identification of the presence of an abnormal adrenal receptor offers the possibility of a new pharmacological approach to control hypercortisolism by suppressing the endogenous ligands or by using specific antagonists of the abnormal receptor.