Although asthma is an inflammatory disorder of the conducting airways involving T(H)2-type T cells, there is increasing evidence for an important role played by the epithelium in orchestrating the inflammatory response by interacting with multiple environmental factors to produce a chronic wound scenario involving tissue injury and aberrant repair. Part of this abnormal response is the consequence of impaired barrier function caused by a primary disruption of epithelial tight junctions that allows inhaled substances to pass more easily into the airway wall to interact with immune and inflammatory cells. Aberrant communication between the damaged and stressed epithelium leads to the generation of growth factors that interact with the underlying mesenchyme to promote airway remodeling responses and a more chronic and persistent inflammatory phenotype. Disordered epithelial function with reduced antioxidant defense and impaired capacity to produce primary IFNs may also account for asthmatic susceptibility to air pollution and respiratory virus infection, respectively. Considering asthma as a disease of impaired barrier function opens new opportunities for therapeutic intervention or prevention by agents that could increase the airways resistance to the inhaled environment rather than suppressing the immune or inflammatory response.