Chagas disease remains an important health problem in Latin America, affecting approximately 8 million to 10 million individuals. This disease originated from an ancient enzootic cycle, and human infection has been detected in 4,000- to 9,000-year-old mummies and has expanded with European colonization, reaching its peak prevalence in the 20th century. Discovered in 1909, the disease remained obscure and uncontrolled until the 1950s, when the generalization of serology, the characterization of chronic cardiomyopathy, and effective insecticides began. By the 1960s, national control programs were launched and incidence began to decrease as a result. During this time, scientific improvements became increasingly available to address disease management. Presently, challenges in managing Chagas disease include maintaining sustainable epidemiological surveillance, the spread of the disease to nonendemic countries, the apparent spread of oral transmission, and new symptoms and manifestations. This review discusses the possibilities and challenges in facing Chagas disease in the coming decades.