The systemic manifestations of severe invasive group A streptococcal infections, such as streptococcal toxic shock syndrome, are mediated by an overwhelming inflammatory response induced by streptococcal superantigens and other virulence factors. The high mortality rates associated with streptococcal toxic shock syndrome demonstrate a need for better therapy in these diseases. Novel strategies to attenuate or prevent streptococcal toxic shock syndrome at different stages of illness have been proposed. The most promising therapies include agents that by various mechanisms attenuate the inflammatory response or the action of streptococcal toxins/superantigens, or both.