Adult mouse mutants homozygous for an engineered proopiomelanocortin (POMC) null allele lack morphologically distinct adrenal glands and circulating adrenal hormones (Yaswen et al. Nature Medicine 1999; 5:1066). To understand the basis for this adrenal defect, we compared the development of adrenal primordia in POMC null and littermate controls. While POMC null mutants are born with morphologically normal adrenal glands, they exhibit two defects: first, they do not release corticosterone upon stimulation with exogenous ACTH; and second, their adrenals regress with age and eventually disappear. Reconstitution of POMC null mutants with ACTH does not rescue structure or function. However, neonatal adrenals transplanted to adrenalectomized wild-type littermates are maintained and functional, while wild-type adrenals transplanted to adrenalectomized mutant littermates are not. From these observations we conclude that POMC peptides are not required for prenatal adrenal development nor for postnatal differentiation. POMC peptides in addition to, or other than, ACTH are required for maintenance of adrenal structures and for permitting corticosterone production and/or release upon ACTH stimulation.