In over 10 years since the definition of superantigens, much has been learned about host cell-superantigen interactions. The initial simple set of rules used to define these interactions has given way to a more complex system, in which the activation of multiple cell types can occur as a consequence of superantigen-cell interactions or as a result of bystander effects based on the induction of a specific cytokine milieu. As a consequence, our ideas concerning the ways in which superantigens might be involved in disease are also expanding rapidly. This review highlights some of the many different pathways of superantigen-associated pathogenesis currently under investigation.