Trypanosoma cruzi is the causative agent of Chagas disease. It is responsible for the highest disease burden of any parasitic infection in Latin America. There is no prophylaxis and the only available therapeutic treatments frequently report toxic side-effects. A prophylactic vaccine would provide a valuable tool for reducing the disease burden. Despite this, no vaccine has progressed into clinical testing. A major obstacle has been the lack of available tools to monitor the parasite burden in vivo, particularly during the chronic stage. Here, we have applied highly sensitive bioluminescent imaging technology to develop our understanding of vaccination strategies aimed at combating T. cruzi infection in mice. First, we applied the system to test a viral vectored vaccine, designed to express two leading T. cruzi vaccine targets (ASP2 and TS). Although this reduced the parasite burden during the acute stage (~70%), it had no long term impact on the course of the infection. We then assessed how this outcome compared to protection conferred by drug cured natural infections. We found that the level of protection was considerably greater than that achieved with viral vaccines (>99%, with several instances of sterile protection) and that the degree of protection was associated with the T. cruzi-specific IFN-γ+ T cell response. We also utilised the in vivo bioluminescence model to investigate if induction of gut inflammation could cure chronically infected mice. By administering a chemical inducer of colitis, we assessed the feasibility of eliminating T. cruzi from the colon, a major parasitological niche in the chronic stage. Finally, we sought to develop attenuated parasites to use as tools for studying live attenuated vaccination by generating null mutant strains of T. cruzi using Cas9 genome engineering. This thesis therefore highlights some of the applications of highly sensitive bioluminescent imaging in furthering our understanding of T. cruzi infection and in accelerating the development of vaccines in the pre-clinical stage.