Recently published data have highlighted the global burden of a part of the mortality associated with GAS infection – rheumatic heart disease. The estimated burden ~319,000 does not include the deaths from invasive GAS, estimated at ~140,000, yielding 459,000 deaths annually. This raises GAS infection to among the leading infectious disease causes of death, after TB, HIV, malaria and invasive Streptococcus pneumoniae disease. In addition, antibiotic treatment for acute pharyngitis, which is indicated for GAS associated pharyngitis (but little else) is often given without a true diagnosis, meaning that 70-90% of antibiotic prescriptions for pharyngitis are unnecessary and potentially contributing to antimicrobial resistance. Despite this large burden of disease, group A strep receives approximately 0.04% of total neglected disease research funding. Work on group A strep vaccines stopped in the late 1970's after a proof of concept human challenge model demonstrated protection, but a clinical trial of a poorly characterized vaccine yielded potential enhancement of non-suppurative complications of GAS infection. Several factors, have impeded GAS vaccine development: funding, concern regarding autoimmune reactions to vaccine, valency issues regarding potential sero/genotype coverage, disappearance of non-suppurative complications of GAS infection from high income countries, and a lack of commercial interest. Recently WHO has initiated work on an R&D Roadmap and a primary product characteristics statement. Mulitvalent M protein vaccines based have been tested in humans; similarly non-M based approaches have also been used. None of these vaccines has been tested for efficacy. As a final consideration, it may be difficult to show that a vaccine prevents either acute rheumatic fever or, ultimately, rheumatic heart disease. While GAS pharyngitis is the antecedent for ARF and RHD, pathogenesis of the latter occurs over decades, and it is not clear that prevention of GAS pharyngitis by vaccination will necessarily lead to a reduction in RHD. This issue may then complicate eventual licensure and uptake of a GAS vaccine despite efficacy against pharyngitis.