Aero-allergens, including plant pollens, house dust mite particles, fungal spores, and mycelium fragments, are continuously inhaled and deposited on the airway mucosa. These particles and their soluble components actively interact with innate recognition systems present in the mucosal layer (e.g., surfactant proteins) and with various receptors present on a diversity of cells in the airways. Deposited particles are first removed by active transportation, the rate of which is either enhanced or inhibited by components present in the inhaled substances. Cleaning further depends on innate recognition, beginning with (a) soluble factors released into the mucosal surface layer that bind different bio-organic components; (b) innate receptors on phagocytic cells, alveolar macrophages, and dendritic monocytes; and (c) innate receptors on airway epithelial cells. Different innate receptor families (Toll-like receptors [TLRs], nucleotide-binding oligomerization domain receptors, and protein-activated receptors [PARs]) have been demonstrated on airway cells, including alveolar macrophages, monocytes, dendritic cells, and airway tissue cells (e.g., epithelial cells and mast cells). However, although the functional role of these receptors has been studied for infectious diseases, the functional role for reaction of airways to inhaled bio-organic substances, including allergens, is largely unexplored. Indirect evidence for functional interactions has come from in vivo animal studies, as well as in vitro studies with monocytes, macrophages, and epithelial cells, which have demonstrated release of cytokines and chemokines after contact with allergens such as house dust mite, cat, pollen, and fungi. Most allergens show direct activation of airway epithelial cells, suggesting a role for the innate receptors. However, the role of TLRs, PARs, and other receptors was studied for only a limited number of allergens. Current studies indicate synergistic interactions between members of the same receptor family (TLRs) as well as synergistic interactions between members of different families (TLRs, PARs, and nucleotide-binding oligomerization domain receptors), modulating responses into feed-forward or inhibitory actions. Study of these synergistic interactions and their genetic variations will provide insight regarding how the innate immune system determines the inflammatory reactions of the airways and the outcome of the T-helper-1- and T-helper-2-type responses to inhaled allergens.