The epithelial Na(+) channel (ENaC) is an end-effector of diverse cellular signaling cascades, including those with phosphatidylinositide second messengers. Recent evidence also suggests that in some instances, phospatidylinositides can directly interact with ENaC to increase channel activity by increasing channel open probability and/or membrane localization. We review here findings relevant to regulation of ENaC by phosphatidylinositol 4,5-bisphosphate (PIP(2)) and phosphatidylinositol 3,4,5-triphosphate (PIP(3)). Similar to its actions on other ion channels, PIP(2) is permissive for ENaC openings having a direct effect on gating. The PIP(2) binding site in ENaC involved in this regulation is most likely localized to the NH(2) terminus of beta-ENaC. PIP(3) also affects ENaC gating but, rather than being permissive, augments open probability. The PIP(3) binding site in ENaC involved in this regulation is localized to the proximal region of the COOH terminus of gamma-ENaC just following the second transmembrane domain. In complementary pathways, PIP(3) also impacts ENaC membrane levels through both direct actions on the channel and via a signaling cascade involving phosphoinositide 3-OH kinase (PI3-K) and the aldosterone-induced gene product serum and glucocorticoid-inducible kinase. The putative PIP(3) binding site in ENaC involved in direct regulation of channel membrane levels has not yet been identified.