The epithelial Na⁺ channel ENaC, located at the apical membrane of Na⁺ transporting cells of the cortical collecting duct, plays an important role in the control of Na⁺ homeostasis and blood pressure. It is composed of three homologous subunits (αβγ), each containing two transmembrane domains, a large extracellular loop and short cytosolic N- and C-termini. Each subunit has at its C-terminus a PY-motif (xPPxY), which has been shown to be deleted/mutated in Liddle’s syndrome, an inherited form of human hypertension, and which serves as a binding site for the ubiquitin-protein ligase Nedd4-2. Indeed, we have demonstrated that ENaC is a short-lived protein, which becomes ubiquitinated on its α and γ subunit, and that such ubiquitination regulates ENaC activity. Moreover, we provide evidence that Nedd4-2 governs ENaC in a PY motif-dependent mode, thereby controlling ENaC surface expression. In the cortical collecting duct, ENaC is tightly regulated by aldosterone, but the molecular mechanisms are not well understood. We will discuss new evidence that the interaction between ENaC and Nedd4-2 is under the control of aldosterone.