Infection with the protozoan parasite Trypanosoma cruzi, the agent of Chagas disease, is characterised by a variable clinical course – from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. The variability in disease outcome has been attributed to host responses as well as parasite heterogeneity. In this article, we review studies indicating the importance of immune responses as key determinants of host resistance to T. cruzi infection and the pathogenesis of Chagas disease. Particular attention is given to recent studies defining the role of cognate innate immune receptors and immunodominant CD8+ T cells that recognise parasite components – both crucial for host–parasite interaction and disease outcome. In light of these studies we speculate about parasite strategies that induce a strong and long-lasting T-cell-mediated immunity but at the same time allow persistence of the parasite in the vertebrate host. We also discuss what we have learned from these studies for increasing our understanding of Chagas pathogenesis and for the design of new strategies to prevent the development of Chagas disease. Finally, we highlight recent studies employing a genetically engineered attenuated T. cruzi strain as a vaccine shuttle that elicits potent T cell responses specific to a tumour antigen and protective immunity against a syngeneic melanoma cell line.