Healthy individuals are continuously exposed to fungal biomass, which includes live and dead spores and fungal debris that is entrapped in the airways. In patients with asthma and/or atopy, exposure to fungal biomass might result in age-dependent sensitization and asthmatic reactions. Interaction with Toll-like receptors (TLRs) of the innate immune defense (alveolar macrophages and epithelial cells) and protease-activated receptors (PARs) determine the effectiveness of elimination of fungal material. The association of sensitization to Alternaria with severe asthma is discussed in relation to the age-dependent sensitization, rate of release of allergens from spores, and activity of its proteases. A model is described concerning the influence of polymorphic genes for airway hyperresponsiveness (AHR) and atopy, showing a cumulating influence on susceptibility for allergen-induced asthma, and explaining that fungus-induced airway obstruction is mainly associated with more severe asthma.