<p>Rheumatic heart disease (RHD) is an acquired chronic inflammatory disease of the heart valves. Regarded as an autoimmune sequela of <i>Streptococcus pyogenes</i> infection, RHD is triggered by the development of carditis during acute rheumatic fever and persists as chronic rheumatic valvulitis in a proportion of patients with acute rheumatic fever. Permanent valve tissue damage ensues, often leading to heart failure. Effective interventions for established RHD are lacking and valve surgery is currently the only treatment option. The limited number of therapeutic targets for heart valve diseases reflects the complexities of studying the mechanisms underlying early valve pathobiology. However, technological advances now enable in-depth profiling of peripheral blood and valve tissue samples from people with RHD, opening new avenues to interrogate human-specific disease processes. In this Review, we revisit established immunological principles of RHD pathogenesis in light of emerging studies. We also explore both systemic and tissue-centric research gaps to advance our understanding of disease mechanisms and to identify human-relevant therapeutic strategies for RHD.</p>