The responsiveness of airway smooth muscle is influenced by the functional integrity of the respiratory epithelium. The nature of this regulatory action by the epithelium remains largely unresolved. Several explanations may account for the epithelium-dependent responses induced by numerous stimuli. This review will present and discuss the evidence suggesting that the epithelium generates an inhibitory signal or signals that function to modulate the responsiveness of the underlying smooth muscle. In addition, the possible candidates for the identity of this epithelium-derived relaxing factor or factors will be assessed. Finally, the mechanisms by which the epithelium-derived relaxing factors may act to modulate bronchomotor tone will be discussed.