Streptococcus pyogenes, also known as group A streptococcus (GAS), is most commonly associated with mild, self-resolving infections of the skin and oropharynx. However, dissemination of the bacteria to normally sterile sites within the body can lead to a variety of invasive conditions that are associated with high morbidity and mortality. In addition, the generation of human cross-reactive antibodies in response to lingering GAS infection can result in the development of post-streptococcal autoimmune sequelae that afflict the organs, joints and CNS.