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Chagas disease, caused by the obligate unicellular parasite Trypanosoma cruzi, presents itself in a diverse collection of clinical manifestations, ranging from severe, fatal heart and digestive tract pathologies to unapparent or minor alterations that do not compromise survival. Over the years, a number of mechanisms have been proposed to explain the pathogenesis of chagasic tissue lesions, all of which have faced some criticism or been received with skepticism. This article excludes the autoimmunity hypothesis for Chagas disease because it has been extensively reviewed elsewhere, and summarizes the various alternative hypotheses that have been advanced over the years. For each of these hypotheses, an outline of its main tenets and key findings that support them is presented. This is followed by the results and comments that have challenged them and the caveats that stand on their way to wider acceptance. It is hoped that this writing will draw attention to our shortcomings in understanding the pathogenesis of Chagas disease, which, unfortunately, continues to figure among the most serious health problems of the American continent.