Asthma is increasing in prevalence worldwide as a result of factors associated with a Western lifestyle. The prevalence and chronic nature of the disease represent significant economic burdens. Despite advances in understanding the inflammatory and immunologic components of asthma, there is relatively little understanding of the cellular and molecular mechanisms underlying the structural changes seen in the asthmatic lung (airway remodeling). These changes include hypertrophy of bronchial smooth muscle, transformation of fibroblasts to myofibroblasts, and deposition of subepithelial collagen. Airway remodeling is linked to bronchial hyperresponsiveness to diverse triggers and a steeper trajectory of long-term decrease in lung function in asthmatic patients. Until recently, these remodeling changes have been considered to be secondary phenomena, developing late in the disease process as a consequence of persistent inflammation. We discuss an alternative view of asthma pathogenesis by emphasizing the importance of the airway microenvironment (the epithelial mesenchymal trophic unit) in the origins of the disease. Our proposals are supported by the recent identification of ADAM33 as an asthma susceptibility gene, the expression of which is abundant in airway fibroblasts and smooth muscle but absent from T lymphocytes or inflammatory cells that infiltrate the airway wall in patients with asthma.