The interaction between the airway epithelium and the inhaled environment is crucial to understanding the pathobiology of asthma. Several studies have identified an important role of airway epithelial-derived cytokines, interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), in asthma pathogenesis. These cytokines have been described as “epithelial-derived alarmins” that activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceived damage. Each of the three epithelial-derived alarmins has been implicated in the pathobiology of inhaled allergen-induced airway responses. The best evidence, to date, exists for TSLP, in that a human monoclonal antibody (hMab), which binds TSLP and prevents its engagement with its receptor, resolves airway inflammation in allergic asthmatic subjects and attenuates allergen-induced airway responses. Better understanding the roles that the epithelial-derived alarmins play and how they influence airway immune response may allow the development of novel therapeutics for asthma treatment.