Autoimmunity is influenced by genetic, immune, hormonal, and environmental factors. Viral infections may trigger autoimmunity. It has been established that autoimmunity may be a contributing factor in the pathogenesis of heart disease. Anti-heart autoantibodies have been identified in the sera of patients with heart diseases, as well as in low titers in certain healthy individuals. Nevertheless, the role of humoral immunity in the development of autoimmune heart disease has not been fully established. Anti-myosin autoantibodies appear in several heart diseases such as myocarditis, dilated cardiomyopathy, Chagas' heart disease, Kawasaki disease, rheumatic fever, and ischemic myocardium. The pathogenic role of anti-myosin autoantibodies in heart disease is not fully understood. Moreover, little is known concerning the clinical implications of anti-myosin autoantibodies in heart disease and its prognostic significance. Anti-cardiac myosin autoantibodies were found to cross-react with the β-adrenergic receptor. Studies have reported the effective use of the anti-myosin directed immune-modulating approach in animals with heart disease, although no specific anti-myosin autoantibody therapeutic approach has been attempted in humans. Herein, we review the current knowledge of anti-myosin autoantibodies and the use of targeted immune-modulating therapy in different heart diseases.