Chagas disease, caused by the protozoan Trypanosoma cruzi, has a variable clinical course, ranging from symptomless infection to severe chronic disease with cardiovascular or gastrointestinal involvement or even overwhelming acute episodes. The factors influencing this clinical variability have not been elucidated, but genetic variation of both the host and parasite is likely to be important. Here, Andréa M. Macedo and Sérgio D.J. Pena review the evidence showing a role for the genetic constitution of T. cruzi in determining the clinical characteristics of Chagas disease, and propose a ;clonal-histotropic model' for the pathogenesis of this disease.