Chagas heart disease is caused by infection with the protozoan parasite Trypanosoma cruzi. The apparent absence of parasites from the hearts of most individuals who succumb to this illness has led some to propose an autoimmune basis for disease pathogenesis. This hypothesis has been extremely difficult to test, because other mechanisms of tissue inflammation may coexist in the setting of active infection. Here we review the proposed mechanisms of Chagas disease pathogenesis and present new evidence in support of an autoimmune contribution to cardiac inflammation in the context of these other mechanisms. While we do not yet have a definitive answer to the autoimmunity question, we hope that our views will provide those engaged in the debate fresh perspective on this challenging issue.