Mucociliary clearance is an important primary innate defense mechanism that protects the lungs from deleterious effects of inhaled pollutants, allergens, and pathogens. Mucociliary dysfunction is a common feature of chronic airway diseases in humans. The mucociliary apparatus consists of three functional compartments, that is, the cilia, a protective mucus layer, and an airway surface liquid (ASL) layer, which work in concert to remove inhaled particles from the lung. A synopsis of clinical and pathological observations in patients with cystic fibrosis, primary ciliary dyskinesia, asthma, and chronic bronchitis indicates that abnormalities in each compartment of the mucociliary system can compromise mucus clearance and cause chronic airway disease. However, the mechanisms that lead to deficient mucus clearance are still incompletely understood. Genetically engineered mice with defects in individual elements of the mucociliary apparatus are powerful tools to study the pathogenesis of mucociliary dysfunction in vivo. In this concise review, I assess the pulmonary phenotypes of mouse models with genetically defined abnormalities in ciliary structure/function, mucus production, and ASL regulation, and discuss the results of these animal studies in the context of current pathogenetic hypotheses for mucociliary dysfunction. Recent data driven from these animal studies point to a critical role of ASL dehydration in the pathogenesis of mucociliary dysfunction and chronic airway disease. In mice with airway-specific overexpression of epithelial Na(+) channels (ENaC), which constitute a rate limiting pathway for absorption of salt and water from airway surfaces, ASL depletion caused reduced mucus clearance, and a spontaneous chronic airway disease with mucus obstruction, goblet cell metaplasia, chronic inflammation, reduced bacterial clearance, and high pulmonary mortality. This mouse model of mucociliary dysfunction will allow an in vivo evaluation of novel therapeutic strategies designed to improve mucociliary clearance, and will aid the preclinical development of novel therapies for chronic airway diseases.