Abstract: Mice deficient in proopiomelanocortin peptides (Pomc^−/−) generated on a 129 (A^w/ A^w) genetic background were back‐crossed onto the C57BL/6 (a/a) genetic background. These mice exhibited most of the phenotypic characteristics previously reported on the 129 genetic background (Yaswen et al. 1999. Nat. Med. 5: 1066–1070). Adult mice became obese, their adrenals were atrophied, and they had undetectable plasma corticosterone in basal and stressed states. The partial perinatal lethality previously reported was also present on the C57BL/6 background. In addition, we found that both male and female homozygote (−/−) adults were fertile, but when homozygous males were intercrossed with homozygous females, all the pups died in the perinatal period. Attempts to rescue the perinatal lethality of pups from homozygous breeder pairs by supplementing the mother's drinking water with glucocorticoids were unsuccessful. Furthermore, failure to stimulate adrenal development and corticosterone production/release with daily exogenous adreno‐corticotropin‐stimulating hormone (ACTH) injections indicates an adrenal dependence on POMC peptides for normal development and function. While the original Pomc^−/− mice, bred on a mixed white‐bellied agouti (A^w/ A^w) 129 genetic background, had patchy alternations in their coat color, they clearly were not a uniform yellow like the lethal yellow (A^y/a) mice. Our Pomc^−/− mice bred onto the C57BL/6 (a/a) genetic background had a black coat color indistinguishable from that of the wild‐type C57BL/6 mice, further suggesting that the POMC peptide melanocyte‐stimulating hormone (α‐MSH) is not essential for the production of eumelanin (black/brown) pigmentation.