The past 30 years have witnessed a resurgence of severe Streptococcus pyogenes (group A streptococcus; GAS) invasive disease paralleled with the emergence and global dissemination of the highly virulent M1T1 clone. The GAS M1T1 clone has diverged from the ancestral M1 serotype, by horizontal acquisition of two unique bacteriophages, encoding the potent DNase Sda1/SdaD2 and the superantigen SpeA, and of a 36 kilobase genome segment from serotype M12 GAS, encoding NAD-glycohydrolase and streptolysin O. Recent studies have shown that GAS M1T1 undergo a genetic “switch” in vivo to a hypervirulent state that favours dissemination into sterile sites of the body as a result of mutation within the covRS regulon, leading to resistance to neutrophil-mediated killing promoted by the bacteriophage-encoded DNase. By performing genomic and phenotypic comparison of M1 and M1T1 strains, we demonstrate that acquisition of the 36 kilobase genome segment and bacteriophage-encoded DNase Sda1 leads to increased virulence, while the more recent acquisition of the SpeA superantigen likely provided selection advantage for the global dissemination of the M1T1 clone within Western populations. To confirm the impact of Sda1 carriage on M1T1 virulence, we transferred by lysogenic conversion the Sda1-encoding phage from M1T1 to the non-clonal M1 isolate SF370. Although Sda1 was expressed in SF370 lysogens, the capacity to survive human neutrophil killing and switch to the hyperinvasive covRS mutant form, and to cause invasive lethal infection were unaltered. Concomitantly, we demonstrate that M1 protein and hyaluronic acid capsule are also essential for the switching phenotype and neutrophil resistance. These findings suggest that hypervirulence of M1T1 is due to the unique synergic effect of M1T1 clone-specific virulence factors (Sda1, M1 protein and hyaluronic acid capsule) acting in concert with the M1T1 genomic background to produce the hypervirulent phenotype.