Superantigens are a class of highly potent immuno-stimulatory molecules produced by Staphylococcus aureus and Streptococcus pyogenes. These toxins possess the unique ability to interact simultaneously with MHC class II molecules and T-cell receptors, forming a trimolecular complex that induces profound T-cell proliferation. The resultant massive cytokine release causes epithelial damage and leads to capillary leak and hypotension. The staphylococcal superantigens are designated staphylococcal enterotoxins A, B, C (and antigenic variants), D, E, and the recently discovered enterotoxins G to Q, and toxic shock syndrome toxin-1. The streptococcal superantigens include the pyrogenic exotoxins A (and antigenic variants), C, G – J, SMEZ, and SSA. Superantigens are implicated in several diseases including toxic shock syndrome, scarlet fever and food poisoning; and their function appears primarily to debilitate the host sufficiently to permit the causation of disease. Structural studies over the last 10 years have provided a great deal of information regarding the complex interactions of these molecules with their receptors. This, combined with the wealth of new information from genomics initiatives, have shown that, despite their common molecular architecture, superantigens are able to crosslink MHC class II molecules and T-cell receptors by a variety of subtly different ways through the use of various structural regions within each toxin.