Intercrosses of heterozygous pro-opiomelanocortin (POMC) mice result in homozygous null progeny at lower frequencies than expected. Genotyping offspring at pre-, peri-, and postnatal stages revealed that over half of homozygous null mutants die in the early postnatal stages. To investigate the reasons for this early postnatal lethality, we analyzed in detail different parameters in the initial hours after birth. POMC null mutants born to heterozygous dams presented at birth with corticosterone levels no different from wildtype littermates, were euglycemic, and had normal liver glycogen stores. However, already 30 min after birth corticosterone levels dropped by 80% and were undetectable thereafter, while corticosterone levels in wildtype animals increased during postnatal hours. Circulating adrenaline was almost below detection 1h after birth. Blood glucose levels fell sharply in all genotypes within 30 min after birth; however, wildtype and heterozygous pups overcame hypoglycemia within an hour, while mutant pups stayed hypoglycemic. The depletion of liver glycogen stores in mutant pups was significantly less efficient compared to their littermates in the hours after birth. POMC null mutant mice born to POMC null mutant dams completely lack corticosterone and die of the expected respiratory dysfunction. In contrast, POMC null mutant mice born to heterozygous dams do not die of respiratory problems, but rather due to hypoglycemia. Our studies confirm an essential involvement of POMC peptides and of adrenal glucocorticoids and catecholamines on glucose homeostasis critical for early postnatal survival.