Many organs are functionally sexually dimorphic, resulting in profound differences in the activity of several physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The rodent HPA axis matures post-weaning, characterized by parallel increments in adrenal weight, adrenal cortical size and corticosterone secretion. Between postnatal days (PND) 30 to 45, these parameters increase to a greater extent in females compared to males. Over this same interval, hepatic production of corticosteroid-binding globulin (CBG), a plasma protein that regulates the bioavailability of free, unbound steroid to tissue, also increases to a greater extent in females. Thus, we postulate that variations in CBG contribute to the sexual dimorphism of the HPA axis. To explore this possibility, we produced a unique rat model in which the SerpinA6 gene encoding CBG was disrupted using a CRISPR/cas9 strategy and followed the maturation of the HPA axis in both males and females. Relative to wild type controls, adrenal weight was normal at PND 30, but lower at PND 45, 60 and 90 in female knockout (KO) rats; whereas male KO rats showed no such differentiation. This reduction in adrenal size in the female KO rat was reflected by an equally remarkable change in the adrenal transcriptome. Thus, while female KO adrenals responded to show ˜3500 differentially expressed genes, virtually no differences were observed between male KO and controls. Free corticosterone levels were comparable in controls and KO animals regardless of sex, but only female KO rats displayed a reduction in total corticosterone levels. We conclude that CBG contributes to the ontogeny of sex differences in the HPA axis; and predict that it may also be responsible for the morphogenesis of other glucocorticoid sensitive organ systems.