The pyrogenic toxin (PT) family is composed of the staphylococcal enterotoxins (SE), the toxic shock syndrome toxin, and the streptococcal pyrogenic exotoxins (SPE). Whereas considerable effort has focused on characterization of PTs due to their unique biological properties, our understanding of the evolution of this gene family is incomplete. Phylogenetic relationships for members of the PT family were estimated by examining the previously reported nucleotide sequences of the genes encoding SPEA, SPEC, SEA, SEB, SEC1, SEC2, SEC3, SED, and SEE. Additionally, we present and analyze sequence data on seven previously unreported sec genes. Within the PT family, sequence divergence was partitioned in a hierarchical fashion such that mean sequence divergence ranged from 1.179 among all 16 toxin genes, 0.443 among those restricted to Staphylococcus, and 0.028 among the genes encoding 10 variants of Type C SE. Results of this study are interpreted as suggesting that the PT family consists of two large clades. One clade consists of the staphylococcal toxins SEA, SEE, and SED, being closely related to the streptococcal toxin SPEC, whereas the other clade depicts close relationships of the staphylococcal toxins SEC and SEB with the streptococcal toxin SPEA.