It is well recognized that toxins of Staphylococcus aureus and Streptococcus pyogenes are responsible for a wide range of clinical conditions, although their precise mode of action remains unclear. Recently, there has been a resurgence of interest in these toxins, now grouped with superantigens, because they cause profound alterations in the immune system homeostasis. Superantigens are molecules, including endogenous retroviral gene products and microbial toxins, that share a unique set of characteristics. They bind with high affinity to major histocompatibility complex class II at regions distinct from the conventional antigen binding groove and cause prolific activation or anergy of T cells with certain T cell receptor variable-region gene families. Whilst most of the superantigens described to date are products of bacteria or viruses, the presence of superantigens in parasites and their role in disease pathogenesis remain to be defined. It is probable that associations are present between superantigen-induced proliferation or anergy of peripheral blood T cells and clinical manifestations of human infectious diseases. The identification of these may pave the way toward a better understanding of disease pathogenesis and the possible development of newer immunotherapeutic regimes. This review summarizes the current thinking on microbial superantigens, their association with human T cells, and speculations about their significance.