Superantigens (SAGs) cause a massive T-cell proliferation by simultaneously binding to major histocompatibility complex (MHC) class II on antigen-presenting cells and T-cell receptors (TCRs) on T cells. These T-cell mitogens can cause disease in host, such as food poisoning or toxic shock. The best characterized groups of SAGs are the bacterial SAGs secreted by Staphylococcus aureus and Streptococcus pyogenes. Despite a common overall three-dimensional fold of these SAGs, they have been shown to bind to MHC class II in different ways. Recently, it has also been shown that SAGs have individual preferences in their binding to the TCRs. They can interact with various regions of the variable β-chain of TCRs and at least one SAG seems to bind to the α-chain of TCRs. In this review, different subclasses of SAGs are classified based upon their binding mode to MHC class II, and models of trimolecular complexes of MHC–SAG–TCR molecules are described in order to reveal and understand the complexity of SAG-mediated T-cell activation.