The amiloride-sensitive epithelial sodium channel, ENaC, is a heteromultimeric protein made up of three homologous subunits (α, β and γ)^1,2. In vitro, assembly and expression of functional active sodium channels in the Xenopus oocyte is strictly dependent on αENaC — the β and γ sub-units by themselves are unable to induce an amiloride-sensitive sodium current in this heterologous expression system². In vivo, ENaC constitutes the limiting step for sodium absorption in epithelial cells that line the distal renal tubule, distal colon and the duct of several exocrine glands. The adult lung expresses α, β and γ ENaC^3,4, and an amiloride-sensitive electrogenic sodium reabsorption has been documented in upper and lower airways^3–7, but it is not established whether this sodium transport is mediated by ENaC in vivo. We inactivated the mouse αENaC gene by gene targeting. Amiloride-sensitive electrogenic Na⁺ transport was abolished in airway epithelia from αENaC(−/−) mice. αENaC(−/−) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid. This study shows that ENaC plays a critical role in the adaptation of the newborn lung to air breathing.