Group A Streptococcus (GAS) has long been recognized as a human pathogen causing an exceptionally broad range of infections. However, despite intense research, the molecular mechanisms of GAS disease remain unclear. Recently, many important discoveries have been made that shed light on GAS pathogenesis and open exciting new avenues for future research. Advances in genome sequencing, microarray technology and proteomic analysis in combination with the development of more suitable animal models have dramatically increased the amount of data regarding the mechanisms of GAS pathogenesis. The information gained from these studies will translate into the identification of improved diagnostics and new targets for novel therapeutic drugs and vaccines.