Streptococcus pyogenes (i.e., the group A Streptococcus) is a human-restricted and versatile bacterial pathogen that produces an impressive arsenal of both surface-expressed and secreted virulence factors. Although surface-expressed virulence factors are clearly vital for colonization, establishing infection, and the development of disease, the secreted virulence factors are likely the major mediators of tissue damage and toxicity seen during active infection. The collective exotoxin arsenal of S. pyogenes is rivaled by few bacterial pathogens and includes extracellular enzymes, membrane active proteins, and a variety of toxins that specifically target both the innate and adaptive arms of the immune system, including the superantigens; however, despite their role in S. pyogenes disease, each of these virulence factors has likely evolved with humans in the context of asymptomatic colonization and transmission. In this article, we focus on the biology of the true secreted exotoxins of the group A Streptococcus, as well as their roles in the pathogenesis of human disease.