Knowledge on the mechanisms of acid and base secretion in airways has progressed recently. The aim of this review is to summarize the known mechanisms of airway surface liquid (ASL) pH regulation and their implication in lung diseases. Normal ASL is slightly acidic relative to the interstitium, and defects in ASL pH regulation are associated with various respiratory diseases, such as cystic fibrosis. Basolateral bicarbonate (HCO₃⁻) entry occurs via the electrogenic, coupled transport of sodium (Na⁺) and HCO₃⁻, and, together with carbonic anhydrase enzymatic activity, provides HCO₃⁻ for apical secretion. The latter mainly involves CFTR, the apical chloride/bicarbonate exchanger pendrin and paracellular transport. Proton (H⁺) secretion into ASL is crucial to maintain its relative acidity compared to the blood. This is enabled by H⁺ apical secretion, mainly involving H⁺/K⁺ ATPase and vacuolar H⁺-ATPase that carry H⁺ against the electrochemical potential gradient. Paracellular HCO₃⁻ transport, the direction of which depends on the ASL pH value, acts as an ASL protective buffering mechanism. How the transepithelial transport of H⁺ and HCO₃⁻ is coordinated to tightly regulate ASL pH remains poorly understood, and should be the focus of new studies.