Rheumatic heart disease lesions are mediated by inflammatory and autoimmune reactions. Several genes related to both innate and adaptive immune responses are involved in the development of the disease. Adhesion molecules and chemokines facilitate heart tissue-T cell infiltration. T lymphocytes are the major effectors of crossreactivity between streptococcal and human proteins leading to RHD. The in vitro analysis of heart-tissue infiltrating T cells showed their ability to recognize streptococcal-M protein peptides as well as self-antigens by molecular mimicry mechanism. A cytokine balance favoring Th1 polarization and production of inflammatory cytokines and few IL-4 producing cells in the valves lead to the progression and maintenance of valvular lesions.