Rheumatic heart disease (RHD) constitutes a leading cause of premature death and incapacity in Africa, where it is encountered in younger people, and shows a much faster and more malignant course than that seen in Europe or North America. While it is well established that RHD is a consequence of recurrent, untreated group A β-haemolytic streptococcal infections (GAS), the pathogenesis is incompletely understood, and the variation in natural history and phenotypes are not fully explained. In Africa patients are rarely diagnosed with acute rheumatic fever (ARF). They usually present in the late stages of RHD, with the severe and virulent forms occurring at early ages, therefore leading to high morbidity and mortality in young patients. Evidence suggests that genetic factors may be involved in determining susceptibility to ARF as well as the severity and outcomes of RHD. However, the results of genetic studies have been inconsistent, and conflicting results have been found in series from Africa when compared to other parts of the globe. Genetic studies in the African context are therefore justified to understand the genomic and epigenetic drivers of heterogeneity in individual responses to GAS infections and progression to RHD. Platforms such as the global registry of RHD represent an opportunity for adequately powered genome-wide association studies. The discovery of all genetic susceptibility loci through whole-genome scanning may provide a clinically useful genetic risk-prediction tool that will potentially allow echocardiographic screening and secondary prophylaxis for moderate lesions to be directed to those at higher risk, therefore reducing the burden of the disease to the health system, the work health force and the communities of this resource-strained continent.