Virulence factors are microbial products that are known to be harmful to the host and may assist in the pathogenesis of the micro-organism. Superantigens, including those produced by bacteria and viruses, clearly act as virulence factors. The clinical effects of superantigens can be not only acute but also chronic and complex. Recent evidence suggests that superantigens may play a central role in the pathogenesis of autoimmune and immunodeficiency disorders. It is our contention that superantigens, as environmental factors, can change a controllable disease into one that becomes relentless for susceptible individuals. To illustrate the detrimental effects of superantigens on disease outcome, modulation of experimental allergic encephalomyelitis by superantigen, as well as the potential role of superantigens in human immunodeficiency virus pathogenesis will be discussed. The information presented may provide valuable insight into the role of superantigens in autoimmunity and human immunodeficiency virus infection.