Activity of the epithelial Na⁺ channel (ENaC) is limiting for Na⁺ transport across many epithelia. Consequently, ENaC modulation is central to regulation of systemic blood volume and pressure. ENaC is an end-effector of diverse cellular signaling cascades, including those with phosphatidylinositide second messengers. In some instances, phospatidylinositides directly interact with ENaC to influence channel activity. PI(4,5)P₂ is permissive for ENaC opening having a direct effect on gating. Signaling from G protein coupled receptors and receptor tyrosine kinases decrease the membrane levels of PI(4,5)P₂ to decrease ENaC activity. PI(3,4,5)P₃, a second messenger in the aldosterone to ENaC signaling cascade, also affects channel gating through direct interactions. Rather than being permissive for gating, PI(3,4,5)P₃ increases ENaC open probability. The PI(3,4,5)P₃ binding site in ENaC involved in this regulation is localized to region just following the second transmembrane domain in the C-terminus of the γ-ENaC subunit. This domain contains several conserved positive charged residues. Substitution of these positive residues with neutral amino acids abolishes modulation by PI(3,4,5)P₃. In conclusions, our recent findings demonstrate that binding of phosphatidylinositides to ENaC directly regulate channel gating. This mode of channel regulation may be particularly important for ENaC responses to natriferic hormones, including aldosterone, involved in control of blood volume and pressure.