Epithelial Na⁺ channels are expressed widely in absorptive epithelia such as the renal collecting duct and the colon and play a critical role in fluid and electrolyte homeostasis. Recent studies have shown that these channels interact via PY motifs in the C terminals of their α, β, and γ subunits with the WW domains of the ubiquitin-protein ligase Nedd4. Mutation or deletion of these PY motifs (as occurs, for example, in the heritable form of hypertension known as Liddle’s syndrome) leads to increased Na⁺ channel activity. Thus, binding of Nedd4 by the PY motifs would appear to be part of a physiological control system for down-regulation of Na⁺ channel activity. The nature of this control system is, however, unknown. In the present paper, we show that Nedd4 mediates the ubiquitin-dependent down-regulation of Na⁺ channel activity in response to increased intracellular Na⁺. We further show that Nedd4 operates downstream of G_o in this feedback pathway. We find, however, that Nedd4 is not involved in the feedback control of Na⁺ channels by intracellular anions. Finally, we show that Nedd4 has no influence on Na⁺ channel activity when the Na⁺ and anion feedback systems are inactive. We conclude that Nedd4 normally mediates feedback control of epithelial Na⁺ channels by intracellular Na⁺, and we suggest that the increased Na⁺ channel activity observed in Liddle’s syndrome is attributable to the loss of this regulatory feedback system.