Research on the biology of airway epithelium in the last decades has progressively uncovered the many roles of this cell type during the immune response. Far from the early view of the epithelial layer simply as a passive barrier, the airway epithelium is now considered a central player in mucosal immunity, providing innate mechanisms of first-line host defense as well as facilitating adaptive immune responses. Alterations of the epithelial phenotype are primarily involved in the pathogenesis of allergic airways disease, particularly in severe asthma. Appreciation of the epithelium as target of glucocorticoid therapy has also grown, because of studies defining the pathways and mediators affected by glucocorticoids, and studies illustrating the relevance of the control of the response from epithelium in the overall efficacy of topical and systemic therapy with glucocorticoids. Studies of the mechanism of action of glucocorticoids within the biology of the immune response of the epithelium have uncovered mechanisms of gene regulation involving both transcriptional and posttranscriptional events. The view of epithelium as therapeutic target therefore has plenty of room to evolve, as new knowledge on the role of epithelium in immunity is established and novel pathways mediating glucocorticoid regulation are elucidated.