Lung liquid absorption at birth is crucial for the successful onset of respiration. Na absorption by the renal collecting duct plays an important role in renal fluid and electrolyte homeostasis during the early postnatal period. The epithelial Na channel (ENaC) plays a central role in mediating these functions, and its subunit expression is developmentally regulated in a temporal and tissue specific pattern. Several lines of evidence suggest that the prenatal increase in circulating glucocorticoids may play an important role in increasing ENaC expression during maturation. We tested the role of the prenatal surge using corticotropin-releasing hormone (CRH) knockout (KO) mice. Relative ENaC expression in lungs of KO mice increased at the same rate as in wild-type (WT) mice, but absolute expression was only 20–30% of WT. In contrast, relative and absolute expression of all three subunits in kidneys was not different between KO and WT mice. Dexamethasone (Dex) increased α-ENaC mRNA in fetal lung and kidney explants within 24 h but had different effects on β- or γ-ENaC. Dex increased β- and γ-ENaC in lung, but only after >48 h of exposure, and had no effect on kidney. The results suggest that the kidney metabolizes endogenous glucocorticoids, but the lung does not. Furthermore, the marked difference between lung and kidney responsiveness to glucocorticoids in β- and γ-ENaC expression suggests that factors other than steroids may be important in regulating functional ENaC expression during development.