Dopamine negatively regulates POMC gene expression in melanotrophs of the intermediate lobe of the pituitary gland. The dopaminergic receptor involved in this control is the dopamine D2 receptor (D2R). The principal products of the POMC gene in melanotrophs are β-endorphin and α-MSH. POMC is differently processed in the corticotrophs, where it is not regulated by dopamine and it is principally processed into ACTH. Here we show that D2R-deficient mice have increased POMC expression and intermediate lobe hypertrophy. Strikingly, D2R-deficient mice have unexpected elevated ACTH levels with a corresponding increase of corticosteroids and consequent hypertrophy of the adrenal gland. This phenotype is reminiscent of Cushing’s syndrome in humans. Interestingly, we show that the elevation in ACTH levels is due to an aberrant processing of POMC in melanotrophs. Indeed, we demonstrate that in addition to controlling POMC gene expression in these cells, dopamine, by modulating the expression of the convertases involved in the cleavage of the POMC prohormone, strictly regulates its processing. These results reveal a key role for dopamine in the control of POMC-derived peptides and furthermore indicate an implication of the dopaminergic system in the genesis of Cushing’s syndrome.