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The mechanisms of action and resistance to these drugs in this parasite are not complete known. In order to identify differentially expressed transcripts between sensitive and resistant parasites, a massive pyrosequencing of the <jats:italic>T. cruzi<\/jats:italic> transcriptome was carried out. Additionally, the 2D gel electrophoresis profile of sensitive and resistant parasites was analyzed and the data were supported with functional genomics. The results showed 133 differentially expressed genes in resistant parasites. The transcriptome analysis revealed the regulation of different genes with several functions and metabolic pathways, which could suggest that resistance in <jats:italic>T. cruzi<\/jats:italic> is a multigenic process. Additionally, using transcriptomics, one gene, adenine phosphoribosyltransferase (APRT), was found to be down\u2010regulated in the resistant parasites and its expression profile was confirmed by 2D electrophoresis analysis. The role of this gene in the resistance to Bz was confirmed overexpressing it in sensitive and resistant parasites. Interestingly, both parasites became more sensitive to Bz and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>. This is the first RNA\u2010seq study to identify regulated genes in <jats:italic>T. cruzi<\/jats:italic> associated with Bz resistance and to show the role of APRT in <jats:italic>T. cruzi<\/jats:italic> resistance. Although <jats:italic>T. cruzi<\/jats:italic> regulation is mainly post\u2010transcriptional, the transcriptome analysis, supported by 2D gel analysis and functional genomic, provides an overall idea of the expression profiles of genes under resistance conditions. These results contribute essential information to further the understanding of the mechanisms of action and resistance to Bz in <jats:italic>T. cruzi<\/jats:italic>. J. Cell. 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