Streptococcus pyogenes (group A Streptococcus) is a globally disseminated and human-adapted bacterial pathogen that causes a wide range of infections, including scarlet fever. Scarlet fever is a toxin-mediated disease characterized by the formation of an erythematous, sandpaper-like rash that typically occurs in children aged 5 to 15. This infectious disease is caused by toxins called superantigens, a family of highly potent immunomodulators. Although scarlet fever had largely declined in both prevalence and severity since the late 19th century, outbreaks have now reemerged in multiple geographical regions over the past decade. Here, we review recent findings that address the role of superantigens in promoting a fitness advantage for S. pyogenes within human populations and discuss how superantigens may be suitable targets for vaccination strategies.