Publisher Summary Chronic Chagas' Disease Cardiomyopathy (CCC) is one of the few well-defined examples of human post-infectious autoimmunity, as documented by several groups in over 50 publications. The time scale dissociation between primary infection with high tissue and blood parasitism and tissue pathology, allied to the scarcity of T. cruzi in CCC heart lesions prompted investigators as early as 70 years ago to suggest that the mononuclear cell infiltrate should directly damage the heart in an autoimmune fashion. This chapter discusses evidence for autoimmunity as a major factor for heart tissue damage in CCC. Unraveling the mechanism by which an infectious agent can trigger organ-specific autoimmunity may lead to reverse strategies for identifying putative triggering infectious agents in autoimmune diseases of suspected infectious etiology. In addition, testing current concepts on molecular pathogenesis of human autoimmune disorders on proven post-infectious autoimmune disease like CCC and rheumatic fever may allow the early identification of susceptible individuals and therapy of affected patients.