Trypanosoma cruzi is the etiologic agent of Chagas' disease, an infection that affects several million people in Latin America. With no immediate prospect of a vaccine and problems associated with current chemotherapies, the development of new treatments is an urgent priority. Several aspects of the redox metabolism of this parasite differ enough from those in the mammalian host to be considered targets for drug development. Here, we review the information about a trypanosomatid-specific molecule centrally involved in redox metabolism, the dithiol trypanothione, and the main effectors of cellular antioxidant defense. We focus mainly on data from T. cruzi, making comparisons with other trypanosomatids whenever possible. In these parasites trypanothione participates in crucial thiol-disulfide exchange reactions and serves as electron donor in different metabolic pathways, from synthesis of DNA precursors to oxidant detoxification. Interestingly, the levels of several enzymes involved in trypanothione metabolism and oxidant detoxification increase during the transformation of T. cruzi to its mammalian-infective form and the overexpression of some of them has been associated with increased resistance to macrophage-dependent oxidative killing. Together, the evidence suggests a central role of the trypanothione-dependent antioxidant systems in the infection process.