In gastrointestinal tissues, cumulative evidence from both in vivo and in vitro studies suggests a role for the cystic fibrosis transmembrane conductance regulator (CFTR) in apical epithelial bicarbonate conductance. Abnormal lumenal acidification is thus hypothesized to play a role in the genesis of cystic fibrosis (CF) pancreatic disease. However, consensus regarding CFTR's participation in pH regulation of airway surface liquid (ASL) and thus the contribution of ASL pH to the etiology of CF lung disease, is lacking. The absence of data reflects difficulties in both sampling ASL in vivo and modeling ASL biology in vitro. Here we evaluate the evidence in support of a lumenal acidification hypothesis in the CF lung, summarize current knowledge of pH regulation in the normal airway and illustrate how hyper-acidified airway secretions could contribute to the pathogenesis of CF lung disease.