Understanding the pathways involved in the induction and maintenance of respiratory tolerance to airborne allergens is important in designing new therapies for asthma and other allergic diseases that not only control disease symptoms, but also change or potentially cure the disease. Respiratory tolerance, and mucosal immunity are maintained by a complex system of defense mechanisms. Most of the inhaled environmental load is eliminated by exclusion mechanisms, which include physical barriers, such as mucus, and cilia as well as a variety of mediators with anti-microbial and immunomodulatory properties. Blanket immunosuppression is provided by alveolar macrophages, which inhibit antigen presentation and T cell responses, in addition to their role in pathogen elimination. Furthermore, there is antigen specific unresponsiveness or tolerance. This tolerance is mediated by lung dendritic cells producing IL-10, which induce the development of CD4+ T regulatory cells. The development of respiratory tolerance also depends on co-stimulation (CD86, and the ICOS-ICOSL pathway). Although exposure of the respiratory mucosa to some pathogenic agents (especially virus, and endotoxin) is associated with asthma exacerbations, microbial exposure may also promote mucosal tolerance and protection against the development of allergic diseases, but the mechanisms involved are not very well understood. Mucosal-based immunotherapy has been already used as an alternative form of allergen delivery in immunotherapy, the only available treatment that is able to reverse established allergic disease. Strategies to further improve mucosal immunotherapy include the use of modified allergen derived peptides, and adjuvants like CpG motifs.