(A) In normal airways, CFTR and ENaC coexist in the apical plasma membrane of airway epithelial cells with CaCC, outwardly rectifying Cl^– channel (ORCC), and Cl^– channel 2 (CLC2). Basolateral Na⁺/K⁺-ATPase pumps provide the driving force for active transport, and the Na⁺K⁺2Cl^– cotransporter assists in moving Cl^– across the basolateral membrane. Active Cl^– secretion via CFTR (baseline unstimulated and agonist activated) tempers ENaC-mediated Na⁺ reabsorption. The combination of Cl^– secretion and reduced Na⁺ reabsorption favors a healthy ion composition and depth of airway surface liquid, enabling effective ciliary beat–driven mucociliary clearance. Mucus is secreted from submucosal glands and is propelled by cilia and cough in a proximal direction. (B) In CF airways, CFTR is absent or dysfunctional and ENaC is no longer regulated, leading to hyperabsorption of Na⁺ and an increased driving force for fluid reabsorption. The airway surface liquid depth is reduced, the submucosal glands are hypertrophied, excessive mucus is secreted, and mucociliary clearance becomes impaired. In both CF and non-CF airway epithelial cells, P2Y₂ receptors coexist in the apical membrane and are stimulated by ATP or other purinergic agonists to initiate increased intracellular Ca²⁺. Ca²⁺ signaling stimulates Cl^– secretion through the CaCC pathway. In this issue of the JCI, Coakley et al. (7) show that 17β-estradiol intersects with this pathway. Higher 17β-estradiol levels are sensed through estrogen receptors, and the authors show that Ca²⁺-activated Cl^– secretion is decreased in women with CF at times when 17β-estradiol levels are high. The net result in CF is a worsening degree of airway surface dehydration and decreased mucociliary clearance.