Gram-positive Staphylococcus aureus germs constitutively have the possibility to release classical and egc-locus-derived enterotoxins which show superantigen activity, and effectively modify the functions of T and B cells, eosinophils, and other inflammatory and structural cells. The stimulation may lead to a type 2 T helper cell-polarized eosinophilic inflammation as well as a multiclonal IgE production, aggravating airway disease in the upper and lower respiratory tract. Recently, S. aureus has been demonstrated to reside intraepithelially, and potentially to release superantigens into the tissue from within the epithelial cells. An immune defect, either in the innate or adaptive immunity, might be responsible for this phenomenon. Follicle-like structures and lymphocyte accumulations, specifically binding enterotoxins, can be found within the mucosal tissue. Interestingly also, IgE antibodies to enterotoxins can be found in the majority of aspirin-sensitive patients, in nasal polyps and severe asthma alike. We here summarize the current evidence from animal and human studies for an active role of staphylococcal enterotoxins (SEs) in allergic rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease and finally early childhood wheezing, and discuss the similarities between those disease manifestations. As a principle, the occurrence of IgE antibodies to SEs correlates with disease severity in terms of total IgE formation, inflammatory markers and clinical expression of the disease. Preliminary evidence from animal models underlines the high potency of SEs to induce or modulate disease, and a few pilot intervention trials may serve as proof of concept for the impact of SEs on disease severity. However, therapeutic approaches are so far limited and empirical, and need further improvement to tackle this currently underestimated clinical challenge.