Despite the near disappearance of rheumatic heart disease (RHD) in wealthier nations of the world, this disease continues to cause substantial morbidity and mortality in poor countries worldwide. The burden is projected to be particularly important among residents of urban slums in poor countries. However, the epidemiologic features of RHD in developing countries are poorly understood. RHD is characterized by damage to cardiac valves that is the long-term consequence of an immune process initiated by infection with Streptococcus pyogenes (Group A Streptococcus; GAS). Progression to RHD often takes decades; it would require decades-long prospective studies to observe associations between GAS infections and the outcome of RHD in the same subjects. Therefore, in this dissertation we first attempted to assess the current burden of RHD in Salvador (Chapter 2), a city where more than half of the population is living in slums, by conducting a population-based study of operations performed for cardiac valve disease. We found that a large proportion of valvular surgeries performed in Salvador from 2002-2005 was for RHD. We then wished to investigate possible reasons for the large burden of this disease. It is known that RHD is influenced by biological factors of beta-hemolytic Streptococcus as well as health-care seeking behavior and treatment of streptococcal infections. Therefore, in the third and fourth chapters of this dissertation we focused on the biological factors of Streptococcus, focusing our work to address current hypotheses regarding RHD pathogenesis as found in the literature, such as: 1) the association of infection or colonization with certain streptococcal strain types and clinical outcome; 2) the increased risk of RHD with repeated infections with a diverse set of GAS strains, and 3) the possible association of RHD with Streptococcus spp. other than GAS.