The clinically relevant pathognomonic consequences of human infection by Trypanosoma cruzi are dilation and hypertrophy of the left ventricle walls and thinning of the apex. The major complications and debilitating evolutionary outcomes of chronic infection include ventricular fibrillation, thromboembolism and congestive heart failure. American trypanosomiasis (Chagas disease) poses serious public healthcare and budgetary concerns. The currently available drugs, although effective against acute infection, are highly toxic and ineffective in arresting or attenuating clinical disease symptoms in chronic patients. The development of an efficacious prophylactic vaccine faces many challenges, and progress is slow, despite several years of effort. Studies in animal models and human patients have revealed the pathogenic mechanisms during disease progression, pathology of disease and features of protective immunity. Accordingly, several antigens, antigen-delivery vehicles and adjuvants have been tested in animal models, and some efforts have been successful in controlling infection and disease. This review will summarize the accumulated knowledge about the parasite and disease, as well as pathogenesis and protective immunity. The authors will discuss the efforts to date, and the challenges faced in achieving an efficient prophylactic vaccine against human American trypanosomiasis, and present the future perspectives.