The adrenal gland regulates a number of essential biological functions through production of steroids and catecholamines. Pro-opiomelanocortin (POMC)-derived peptides have been implicated in all aspects of generating, maintaining, and functioning of the adrenal glands. An appreciation for the roles of POMC-derived peptides with respect to the adrenal has been gained from experiments in vitro, and in vivo in different animal models which surgically, pharmacologically, or genetically decrease or increase the amount of POMC peptides available. We recently produced a mouse model with a deletion of the entire coding region of the POMC gene, thus lacking all POMC-derived peptides, from all sources, and at all times. Here we will summarize and discuss the results of traditional in vivo studies on the role of POMC peptides in adrenal development, maintenance, and function in the context of findings in a mouse model genetically lacking all POMC-derived peptides.