A zone of beta-hemolysis surrounding colonies on blood-agar media is a hallmark phenotypic feature of the pathogens group A Streptococcus (GAS) and group B Streptococcus (GBS). In each case, lysis of red blood cells reflects the action of a potent protein exotoxin. Although these toxins have been the subjects of numerous investigations over the years, their purification and molecular identification have proven elusive. These difficulties reflect the instability of hemolytic activity, as both toxins function only in the context of the bacterial surface or certain high molecular weight 'stabilizer' molecules. This review highlights the recent discoveries of two markedly distinct genetic loci, necessary and sufficient for the beta-hemolytic phenotypes of GAS and GBS, respectively. The generation of isogenic GAS and GBS beta-hemolysin-deficient mutants and their analysis using in vitro and in vivo model systems has shown that both toxins function as virulence factors in the pathogenesis of invasive infections.