&bgr;-Adrenergic agonists accelerate the clearance of alveolar fluid by increasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na+channels (ENaC) and Na,K-ATPases. Here we report that adenoviral-mediated overexpression of a human &bgr;2-adrenergic receptor (&bgr;2AR) cDNA increases &bgr;2AR mRNA, membrane-bound receptor protein expression, and receptor function (procaterol-induced cAMP production) in human lung epithelial cells (A549). Receptor overexpression was associated with increased catecholamine (procaterol)-responsive active Na+transport and increased abundance of Na,K-ATPases in the basolateral cell membrane. &bgr;2AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound &bgr;2AR expression and function and increased levels of ENaC (&agr; subunit) abundance and Na,K-ATPases activity in apical and basolateral cell membrane fractions isolated from the peripheral lung, respectively. Alveolar fluid clearance (AFC), an index of active Na+transport, in &bgr;2AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expresses no cDNA. The addition of the &bgr;2AR-specific agonist procaterol to &bgr;2AR overexpressing lungs did not increase AFC further. AFC in &bgr;2AR overexpressing lungs from adrenalectomized or propranolol-treated rats revealed clearance rates that were the same or less than normal, untreated, sham-infected controls. These experiments indicate that alveolar &bgr;2AR overexpression improves &bgr;2AR function and maximally upregulates &bgr;-agonist–responsive active Na+transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation of &bgr;2AR function may someday prove useful for the treatment of pulmonary edema.