Clearance of mucus is an important function of the airways to maintain hygiene. In disease, persistent inflammation leads to excessive production of mucus, with high viscoelasticity and adhesivity, which is not easily transported by cilia or cough interactions. Accumulated mucus in the airways can lead to airway obstruction, bacterial colonisation, and recurrent infections, resulting in poor quality of life and increased morbidity and mortality. Hyperosmolar agents have the potential to alter the physical properties of mucus and facilitate its clearance by increasing the water in the airway lumen and by reducing the entanglements of the mucin network. Clinical studies using radioaerosols, and imaging with a gamma camera, have demonstrated that hypertonic saline (HS; 3-14.4%) and mannitol (300-400 mg) increase clearance of mucus acutely in patients with mild asthma, bronchiectasis, and cystic fibrosis (CF). Further, in sputum studies, a reduction in the viscoelastic properties, surface tension and spinnability and an increase in the hydration of mucus have been measured in response to HS, mannitol, and other sugars. Inhalation of mannitol (400 mg) twice daily over 2 weeks improved the quality of life significantly in patients with bronchiectasis. Inhalation of 7% HS, four times daily, over 2 weeks improved significantly the baseline mucus clearance rate and lung function in CF patients. In addition, inhalation of 7% HS twice daily over 12 months showed similar results to the short-term studies without a change in the bacterial load in CF patients. Further studies of the long-term clinical effect of hyperosmolar agents are needed.