The role of streptococcal infections in initiating the diverse clinical and pathological manifestations of rheumatic fever and rheumatic heart disease is considered in relation to the multiple cross-reactive relations of group A Streptococcus and tissue antigens. Autoantibodies to the following shared antigens have been demonstrated in sera of patients with rheumatic fever: (1) cardiac, skeletal, and smooth muscle; (2) heart valve fibroblasts; (3) neurons in basal ganglia; and (4) a group A carbohydrate-related determinant in connective tissues. Circulating autoantibodies to these different antigens were present in higher titer or occurred more frequently in patients with rheumatic fever than in those with uncomplicated streptococcal infections. A direct correlation of the presence of these autoantibodies with carditis could not be established. The pathogenetic mechanisms that link streptococcal infection to rheumatic fever and rheumatic heart disease are not yet clear. Among the possibilities to be considered within the above frame of reference are combined cell-mediated and humoral autoimmune mechanisms directed to one or more cross-reactive antigens in the tissues, selective binding of streptococci to tissues, role of circulating immune complexes, and linkage with histocompatibility antigens.