Staphylococcus aureus and streptococci secrete a large family of exotoxins involved in the pathogenesis of toxic-shock-like syndromes and have been implicated in several autoimmune disorders. These toxins act as prototypic superantigens capable of binding to major histocompatibility complex proteins on antigen-presenting cells outside the antigen peptide-binding groove and can thereby stimulate cytokine release from macrophages. The superantigen-major histocompatibility complex unit is recognized primarily by the variable region of the T-cell receptor beta chain, and by engaging this region, can activate a large portion of the T-cell repertoire. It is thought that the capacity of these toxins to cause the massive stimulation of T cells and accessory cells such as macrophages, Langerhans cells, and activated keratinocytes accounts for most of their pathologic effects. The current review examines the evidence that implicates a role for these superantigens in the pathogenesis of certain skin diseases.