Trypanosoma cruzi is the etiological agent of Chagas disease, usually transmitted by triatomine vectors. An estimated 20 to 30% of infected individuals develop potentially lethal cardiac or gastrointestinal disease. Sylvatic transmission cycles exist in the southern United States, involving 11 triatomine vector species and infected mammals such as rodents, opossums, and dogs. Nevertheless, imported chronic T. cruzi infections in migrants from Latin America vastly outnumber locally acquired human cases. Benznidazole is now FDA approved, and clinical and public health efforts are under way by researchers and health departments in a number of states. Making progress will require efforts to improve awareness among providers and patients, data on diagnostic test performance and expanded availability of confirmatory testing, and evidence-based strategies to improve access to appropriate management of Chagas disease in the United States.