Chagas heart disease develops in approximately one-third of individuals infected with the protozoan parasite Trypanosoma cruzi. Among the many possible mechanisms responsible for this illness, an autoimmune mechanism has received much experimental support during the past several decades. Initial observations of the absence or near absence of parasites from the inflamed tissues suggested the autoimmunity hypothesis, and the finding of measurable autoimmune responses in humans and experimental animals has bolstered this idea. The rigorous testing of the hypothesis has been difficult, primarily because other mechanisms are likely to play a role during active infection, particularly immunity to parasite antigens that may persist in the infected animal. While the role autoimmunity plays in disease pathogenesis is not known, it is clear that autoimmune responses are induced during infection of some humans and animals. A number of mechanisms may explain the induction of autoimmunity during T. cruzi infection, including parasite-induced polyclonal lymphocyte activation, molecular mimicry, bystander activation, and presentation of cryptic self epitopes. The genetic makeup of both the parasite and host are also critical to the outcome of infection. The autoimmune hypothesis deserves further exploration, while public health interventions should focus on control of the insects that transmit the parasite, development of parasiticidal drugs and vaccines, and testing of blood products, which have become an important threat of new infections.