Prior studies have shown that the catalase-deficient pathogen Streptococcus pyogenes (group A streptococcus) has a robust ability to resist oxidative stress that partially involves the transcriptional regulator PerR. However, the extent of the PerR regulon and the contribution of the members of this regulon to virulence are unknown. In this study, DNase I footprinting revealed that PerR binds specifically to a single site upstream of the promoter for the gene encoding alkyl hydroperoxide reductase (ahpC). However, analyses of transcript abundance revealed that while ahpC is regulated in response to growth phase, its regulation is independent of PerR. Instead, PerR regulates transcription of a divergent gene cluster that encodes a putative cold shock protein. The gene encoding the Dps-like peroxide resistance protein MrgA was repressed by PerR, consistent with the presence of a PerR binding site in its promoter. Phenotypic analyses of PerR–, AhpC– and MrgA– mutants revealed that while AhpC is not essential for resistance to challenge with hydrogen peroxide in vitro, AhpC does contribute to scavenging of endogenous hydrogen peroxide and is required for virulence in a murine model of infection. In contrast, a MrgA– mutant was hypersensitive to challenge with peroxide in vitro, but was fully virulent in all animal models tested. Finally, a PerR– mutant was hyper-resistant to peroxide, yet was highly attenuated for virulence in all murine models. These data demonstrate that while a mutant's capacity to resist peroxide stress did not directly correlate with its ability to cause disease, the appropriate regulation of the peroxide stress response is critical for virulence.