Superantigens are a group of bacterial and viral proteins that are characterized by their capacity to stimulate a large number of T cells. They bind directly to the major histocompatibility complex class II molecule on the antigen-presenting cell and cross-link the antigen-presenting cell with T cells expressing certain T-cell receptors, leading to polyclonal T-cell activation. They have been shown to play a role in toxic shock syndrome and mucocutaneous lymph node syndrome and are postulated to play a role in other systemic diseases. Because inflammatory skin diseases such as atopic dermatitis and psoriasis are often known to be colonized with superantigen-releasing Staphylococcus aureus, the role of superantigens in skin diseases is of major importance. Recent studies have demonstrated that if a staphylococcal superantigen is applied on intact human skin, a clinical picture of dermatitis evolves. Furthermore, in the presence of superantigens, epidermal cells potently activate T cells. Thus, superantigens may play a role in the induction and exacerbation of inflammatory skin diseases.