Epidemiological studies have identified non-random associations between certain group A Streptococcus (GAS) serotypes and disease phenotypes. For example, serotype M3 isolates are associated with particularly severe and lethal invasive infections, serotype M18 isolates are associated with outbreaks of acute rheumatic fever, and serotype M28 isolates are associated with cases of puerperal sepsis. In my talk I will review my lab’s work identifying the molecular basis behind why M3 GAS isolates are associated with severe invasive infections. We have identified that, since at least the 1920s, there has been a rewiring of regulatory networks in M3 isolates such that they have a serotype-specific virulence factor expression profile. In total we have identified four regulatory systems that, due to mutation or sequence variation, have altered activity in M3 isolates. I will discuss the regulatory and virulence consequences of each system, and how they impact disease potential. Insights into the functionality of these systems will also be provided. Our data are consistent with alterations in gene expression being the driving force behind the association of serotype M3 GAS isolates with particularly severe invasive infections.