Genetic epidemiological approaches hold great promise for improving the understanding of the determinants of susceptibility to infection with Trypanosoma cruzi and the causes of differential disease outcome in T. cruzi-infected individuals. To date, a variety of approaches have been used to understand the role of genetic factors in Chagas disease. Quantitative genetic techniques have been used to estimate the heritabilities for seropositivity for T. cruzi infection and traits that are associated with disease progression in chronic T. cruzi infection. These studies have demonstrated that a significant proportion of the variation in seropositivity and a number of traits related to Chagas disease progression is attributable to genetic factors. Candidate gene studies have provided intriguing evidence for the roles of numerous individual genes in determining cardiac outcomes in chronically infected individuals. Recent results from a long-term study of Chagas disease in a rural area of Brazil have documented that over 60% of the variation in seropositivity status is attributable to genetic factors in that population. Additionally, there are significant genetic effects on a number of electrocardiographic measures and other Chagas disease-related traits. The application of genome-wide approaches will yield new evidence for the roles of specific genes in Chagas disease.