Summary: The airway epithelial cell is the initial cell type impacted both by inhaled environmental factors, such as pathogens, allergens, and pollutants, and inhaled medications for airway diseases. As such, epithelial cells are now recognized to play a central role in the regulation of airway inflammatory status, structure, and function in normal and diseased airways. This article reviews our current knowledge regarding the roles of the epithelial cell in airway inflammation and host defense. The interactions of inhaled environmental factors and pathogens with epithelial cells are also discussed, with an emphasis on epithelial innate immune responses and contributions of epithelial cells to immune regulation. Recent evidence suggesting that epithelial cells play an active role in inducing several of the structural changes, collectively referred to airway remodeling, seen in the airways of asthmatic subjects is reviewed. Finally, the concept that the epithelium is a major target for the actions of a number of classes of inhaled medications is discussed, as are the potential mechanisms by which selected drugs may alter epithelial function.