Staphylococcal exotoxins, staphylococcal enterotoxins A-E (SEA-SEE), and toxic shock syndrome toxin- (TSST-1) are potent activators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to shock. These toxins are called superantigens because of their ability to polyclonally activate T cells at picromolar concentrations. Superantigens bind to both MHC class II molecules and specific Vbeta regions of the T cell receptor, leading to the activation of both antigen-presenting cells and T lymphocytes. These interactions lead to excessive production of proinflammatory cytokines and T cell proliferation, causing clinical symptoms that include fever, hypotension, and shock. Recent studies suggest that staphylococcal superantigens may also be involved in the pathogenesis of arthritis and other autoimmune disorders. This review summarizes the in vitro and in vivo effects of staphylococcal enterotoxins and TSST-1, recent progress with the use of transgenic knockout mice to identify key mediators and receptors involved in superantigen-induced shock, and therapeutic agents to mitigate the toxic effects of staphylococcal superantigens.