Chronic airway infection and inflammation are hallmarks of cystic fibrosis (CF) pulmonary disease. The altered airway environment resulting from infection and inflammation can affect the innate defense of the airway epithelia. Luminal bacterial and inflammatory stimuli trigger an adaptation in human airway epithelia, characterized by a hyperinflammatory response to inflammatory mediators, which is mediated by an expansion of the endoplasmic reticulum (ER) and its Ca²⁺ stores. Recent studies demonstrated that a form of ER stress, the unfolded protein response (UPR), is activated in airway epithelia by bacterial infection–induced airway inflammation. UPR-dependent signaling is responsible for the ER Ca²⁺ store expansion-mediated amplification of airway inflammatory responses. These studies highlight the functional importance of the UPR in airway inflammation and suggest that targeting the UPR may be a therapeutic strategy for airway diseases typified by chronic inflammation. This article reviews the contribution of airway epithelia to airway inflammatory responses, discusses how expansion of the ER Ca²⁺ stores in inflamed airway epithelia contributes to airway inflammation, describes the functional role of the UPR in these processes, and discusses how UPR activation might be relevant for CF airways inflammatory disease.