Mast cells play a central role in orchestrating the complex pathophysiological processes underlying asthma and other allergic diseases. Mast cells present in the airways of chronic asthmatic subjects are present in a chronically activated state, with the ongoing release of a plethora of autacoid mediators, cytokines and proteases. These contribute to airway smooth muscle dysfunction, inflammatory cell recruitment and tissue remodelling. In asthmatic airways, mast cells infiltrate the airway epithelium, airway mucosal gland stroma, and the airway smooth muscle bundles. This therefore places activated mast cells in direct contact with these dysfunctional airway components. Recent ex vivo work using primary human airway cells has identified important bi-directional interactions between mast cells, airway smooth muscle cells and the airway epithelium. Manipulating the pathways which facilitate mast cell-structural cell cross-talk may offer novel approaches to the treatment of asthma and related allergic diseases.