Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are major health problems in many developing countries and Indigenous populations of developed countries. ARF and RHD are sequelae resulting from an infection of Streptococcus pyogenes. Despite advances in health care practices and technology, these diseases still pose major challenges in the communities where Streptococcus pyogenes is often endemic. Here we review and discuss the dynamic epidemiology of streptococcal infection and its associated diseases (ARF and RHD), with a focus on disease burden in temperate versus tropical regions, the tissue tropism of the organism and the efforts towards vaccine development in relation to the available animal models.