Superantigens are polypeptide molecules produced by a broad range of infectious microorganisms which elicit excessive and toxic T-cell responses in mammalian hosts. In light of this property and the fact that autoimmune diseases are frequently the sequelae of microbial infections, it has been suggested that superantigens may be etiologic agents of autoreactive immunological responses resulting in initiation, exacerbation or relapse of autoimmune diseases. This article relates the biology of superantigens to possible mechanisms by which they may exert these activities and reviews the evidence for their roles in various human and animal models of autoimmune disease. Finally, a mechanism of active suppression by superantigen-activated CD4+ T-cells that could be exploited for therapy as well as prophylaxis of human autoimmune diseases is proposed.