In health, the glucose concentration of airway surface liquid (ASL) is 0.4 mM, about 12 times lower than the blood glucose concentration. Airway glucose homeostasis comprises a set of processes that actively maintain low ASL glucose concentration against the transepithelial gradient. Tight junctions between airway epithelial cells restrict paracellular glucose movement. Epithelial cellular glucose transport and metabolism removes glucose from ASL. Low ASL glucose concentrations make an important contribution to airway defense against infection, limiting bacterial growth by restricting nutrient availability. Both airway inflammation, which increases glucose permeability of tight junctions, and hyperglycemia, which increases the transepithelial glucose gradient, increase ASL glucose concentrations, with the greatest effect seen where they coexist. Elevated ASL glucose drives proliferation of bacteria able to use glucose as a carbon source, including Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacteria. Clinically, this appears to be important in driving exacerbations of chronic lung disease, especially in patients with comorbid diabetes mellitus. Drugs can restore airway glucose homeostasis by reducing the permeability of tight junctions (eg, metformin), increasing epithelial cell glucose transport (eg, β-agonists, insulin), and/or by lowering blood glucose (eg, dapagliflozin). In cell culture and animal models these reduce ASL glucose concentrations and limit bacterial growth, preventing infection. Observational studies in humans indicate that airway glucose homeostasis-modifying drugs could prevent chronic lung disease exacerbations if tested in randomized trials. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.