Rheumatic fever (RF), caused by untreated group A streptococcal (GAS) pharyngitis, is a major cause of morbidity and mortality throughout much of the less developed world and disadvantaged populations (Indigenous and other) in the developed world. Through systematic literature searches, our group has identified potential risk factors for RF and possible interventions for its prevention. The causes can be divided into biological factors, socio-economic, and lifestyle factors and health-care systems and services. Currently, the most promising medical areas look to be improving access to health care and introducing community and school-based sore throat interventions (which aim to diagnose and treat GAS pharyngitis). We could find no convincing support for skin sepsis causing RF. Overall evidence suggests that measures that aim to alleviate poverty and crowding may also reduce the incidence of RF. In comparatively rich countries such as New Zealand and Australia, urgent measures based on available evidence should be undertaken to reduce the very striking health disparity seen with RF and its sequela, rheumatic heart disease in our at-risk populations.