The protozoan parasite Trypanosoma cruzi establishes lifelong, chronic infection within most mammalian hosts and can be the driver for symptomatic Chagas disease in humans. CD8+ T cells are essential for the control of T. cruzi infection but the epitope specificity of T cells that mediate that control and/or have the capacity to provide protection is unclear. Vaccination studies have largely focused on enhancing immune responses to epitopes from variable trans-sialidase (TS) gene family proteins, known to be targets of T. cruzi-specific CD8+ T cell responses in both infected mice and humans. However, no vaccine to-date has induced immunity capable of parasite clearance. Further, two immunodominant TS-specific (TSKb18/TSKb20) CD8+ T cell responses elicited during infection of C57BL/6 mice are entirely dispensable for immune control, suggesting a minimal role for these responses in parasite control. These results, combined with the significant variability of TS genes among the various T. cruzi strains, have prompted interest in the identification of novel T cell epitopes derived from conserved, non-TS genes that may potentially serve as more effective and protective targets of CD8+ T cell immunity. Here, we show that the screening of conserved flagellar proteins for T cell epitopes unexpectedly revealed a high level of cross-reactivity within the TSKb20-specific CD8+ T cell response. Despite this broad reactivity, there was no apparent impact on the ability of TSKb20-specific CD8+ T cells to respond to a reinfection, suggesting that cross-reactive potential likely does not detract from effective T cell immunity and may even be a common feature of TCRs. In a second approach for new T cell epitope discovery, a genome-wide screen of non-TS genes was used to identify a novel epitope from proteins of the mucin gene family named MUCKb25, which elicit an immunodominant CD8+ T cell response during infection. The MUCKb25 response, however, was not protective and was entirely dispensable for immune control, indicating that the major targets of the T. cruzi-specific CD8+ T cell response are not protective and may even limit or prevent the generation of more effective CD8+ T cell responses capable of parasite clearance.