The recent discovery of the mode of interaction between a group of microbial proteins known as superantigens and the immune system has opened a wide area of investigation into the possible role of these molecules in human diseases. Superantigens produced by certain viruses and bacteria, including Mycoplasma species, are either secreted or membrane-bound proteins. A unique feature of these proteins is that they can interact simultaneously with distinct receptors on different types of cells, resulting in enhanced cell-cell interaction and triggering a series of biochemical reactions that can lead to excessive cell proliferation and the release of inflammatory cytokines. However, although superantigens share many features, they can have very different biological effects that are potentiated by host genetic and environmental factors. This review focuses on a group of secreted pyrogenic toxins that belong to the superantigen family and highlights some of their structural-functional features and their roles in diseases such as toxic shock and autoimmunity. Deciphering the biological activities of the various superantigens and understanding their role in the pathogenesis of microbial infections and their sequelae will enable us to devise means by which we can intervene with their activity and/or manipulate them to our advantage.