The clinical development of multivalent group A streptococcal (GAS) M protein subunit vaccines has involved three previous clinical trials and one ongoing phase 1 study that have enrolled a total of 164 adult volunteers. The results indicate that the vaccines are safe, well tolerated, and immunogenic. In pre-clinical studies, the current 30-valent vaccine elicited antibodies that cross-opsonized a significant number of non-vaccine emm types of GAS, indicating that vaccine coverage may be sufficient for global deployment. The next steps in the clinical development plan will include an additional safety and immunogenicity study in adults, an age step-down and dose-finding protocol in children and adolescents, and a proof-of-concept efficacy trial in subjects ages 7-14 years, with prevention of pharyngitis as the clinical endpoint. To support future clinical studies, we have successfully adapted the high-throughput HL-60 OPK assay to assess functional antibody activity using multiple GAS emm types. The ongoing development of next-generation vaccines is based on the recent emm cluster typing system that revealed the structural and functional similarities among the M proteins. Computational structure-based design facilitates identification and selection of a minimum number of M peptides from each cluster that evoke antibodies that cross-react with all emm types in the cluster. Application of structure-based vaccine design may result in a broadly protective vaccine that will have a significant impact on the morbidity and mortality associated with GAS infections and their complications.