Superantigens (SAgs) are a family of highly potent mitogens that share the ability to trigger excessive stimulation of human and other mammalian T lymphocytes. This leads to a massive release of T cell mediators and pro-inflammatory cytokines contributing to diseases such as toxic shock syndrome. In contrast to conventional peptides, SAgs bind as unprocessed molecules to major histocompatibility (MHC) class II molecules outside the peptide-binding groove and sequentially to the variable β-chain of the T cell receptor (TcRVβ). Currently, thirteen Streptococcus pyogenes SAgs are described in the literature. Together with the SAgs produced by Staphylococcus aureus, they build a larger family of structurally related, heat-stable exotoxins.