Trypanosoma cruzi, the causal agent of Chagas disease, is an intracellular protozoan parasite that predominantly invades macrophages and cardiomyocytes, leading to persistent infection. Several members of the Toll-like receptor family are crucial for innate immunity to infection and are involved in maintaining tissue homeostasis. This review focuses on recent experimental findings of the innate and adaptive immune response in controlling the parasite and/or in generating heart and liver tissue injury. We also describe the importance of the host’s genetic background in the outcome of the disease and emphasize the importance of studying the response to specific parasite antigens. Understanding the dual participation of the immune response may contribute to the design of new therapies for Chagas disease.