Staphylococcus aureus (S. aureus) is correlated with the development of persistent severe inflammatory disease of the upper airway including chronic rhinosinusitis with nasal polyps. This inflammation of the upper airways is characterized by a T-helper 2-driven disease: interleukin-5 is significantly increased and local production of immunoglobulin E is observed. S. aureus and its enterotoxins are deregulating the tissue inflammation at different levels: structural cells and the innate and adaptive immune system. Knowing the triggers of the pathomechanisms involved will greatly help us to find new therapeutic approaches to resolve this chronic inflammatory process.