This review investigates about the role of Staphylococcus Aureus (S. aureus) and S. aureus enterotoxins (SEs) in the pathogenesis of several chronic airway diseases. S. aureus is part of normal human flora and may colonize the skin and the upper airways. SEs acting as superantigens can induce an intense T cell activation and through the release of interleukin (IL) - 4, 5, and 13, can promote a polyclonal IgE response and eosinophilic inflammation. S. aureus can damage epithelial cells inducing the release of the so-called "alarmins" responsible of the activation of Type 2 innate lymphoid cells (ILC-2) linked to an IL-5 mediated airway eosinophilic inflammation. SEs sensitization has been recently associated with the eosinophilic endotypes of both nasal polyps and late onset severe asthma. Studies investigating the effect of biological therapies in SEs sensitized patients should be performed in order to better define the role played by S. aureus in the different endotypes of severe asthma and/or chronic rhinosinusitis.