The molecular mechanism of Staphylococcus aureus phathogenicity is complex and involves several toxins, including the famous staphylococcal enterotoxin (SE) and toxic shock syndrome toxin-1 (TSST-1). Although these toxins were discovered in specific clinical contexts of food poisoning and menstrual toxic shock syndrome, they share common biochemical and biological properties. As superantigens they are able to massively activate mononuclear cells and T cells regardless of the antigenic specificity of the T cells. To date, 19 different enterotoxins and related toxins have been described in S. aureus with some differences in structure and biological activity. It has been clearly demonstrated that most human S. aureus isolates harbor at least one gene encoding for these toxins. It is suspected that S. aureus produces SEs and TSST-1 in humans from colonization to infection, whatever the clinical situation. It is proposed that the production of SEs plays a role not only in classical staphylococcal infections but also in noninfectious diseases. This review will focus on recent findings related to staphylococcal superantigens and their impact on human diseases.