Aerosolized medications are used as airway clearance therapy to treat a variety of airway diseases. These guidelines were developed from a systematic review with the purpose of determining whether the use of these medications to promote airway clearance improves oxygenation and respiratory mechanics, reduces ventilator time and ICU stay, and/or resolves atelectasis/consolidation compared with usual care. Recombinant human dornase alfa should not be used in hospitalized adult and pediatric patients without cystic fibrosis. The routine use of bronchodilators to aid in secretion clearance is not recommended. The routine use of aerosolized N-acetylcysteine to improve airway clearance is not recommended. Aerosolized agents to change mucus biophysical properties or promote airway clearance are not recommended for adult or pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough. Mucolytics are not recommended to treat atelectasis in postoperative adult or pediatric patients, and the routine administration of bronchodilators to postoperative patients is not recommended. There is no high-level evidence related to the use of bronchodilators, mucolytics, mucokinetics, and novel therapy to promote airway clearance in these populations.