Chagas' disease, a debilitating condition inflicting millions of people in Latin America, is caused by infection with the protozoan parasite Trypanosoma cruzi. One characteristic sequel to the subdued acute infection is electocardiographic alterations in about one third of the patients that reach the chronic phase of disease. Another feature of chronic Chagas' disease is the paucity of parasites in the diseased heart. There have been many debates whether chronic chagasic cardiomyopathy (CCC) is a consequence of parasite persistence or autoimmunity, a central question that will clearly influence the strategies for disease prevention and treatment. In this review, we summarize the pros and cons of each side and provide a novel view on the genesis, and hence treatment of, CCC. In particular, we emphasize the contribution of parasite-derived danger signal, such as parasitokines, to the breakdown of self-tolerance in T. cruzi infection. Accordingly, we argue that a more efficient way of countering immune subversion and autoimmune responses induced by the parasite would be targeting key parasitokines rather than blocking parasitic epitopes cross-reactive with host antigens. Finally, based on current knowledge on immune regulation, especially in transplantation models, we propose that future focus of CCC treatment should rely on efforts to restore the immunological tolerance to self-antigens concurrent with regimens to reduce the parasite load as much as possible through immunological and chemotherapy procedures.