Epithelial cells in the airway wall actively interact with environmental antigens/allergens, both in healthy individuals and patients with asthma. In patients with (allergic) asthma, the epithelium is abnormal, showing damaged structures and continuous activation similar to a repair phenotype cell. Epithelial cells bind allergens by a diversity of innate receptors, similar and in part identical to the Toll-like receptor family, which can induce the release of cytokines, chemokines, and growth factors. Protease-containing extracts (house dust mite, fungi) may additionally cause damage of the epithelial cell layer, thereby enhancing the repair phenotype of epithelial cells in patients with asthma. These interactions may result in facilitation of transport of allergens and enhanced presentation to the immune system (Th2-type response). The inflammatory response induces a second phase of Th2-type cytokines and cytotoxic products that will enhance growth factor-mediated airway remodeling, as is found in asthma. An understanding of the largely unknown innate responses of epithelial cells with environmental antigens/allergens may open new treatment modalities for asthma and other airway diseases.