The historical processes involved in Chagas disease transmission relate to the patterns and conditions of human settlements, especially in rural areas, due to proximity to forest areas, where both vectors and Trypanosoma cruzi can occur, combined with precarious housing conditions and underlying poverty. However, seasonal and permanent rural-urban migration has played a major role in re-mobilizing vectors, T. cruzi, and Chagas-infected individuals. A new agricultural frontier in the Amazon has led to a new transmission pattern, especially with palm trees located close to houses. Improved blood bank surveillance has decreased transmission by blood transfusions. International migration also plays a role in Chagas disease epidemiology. The United States and Spain, where specific health services for Chagas disease diagnosis and treatment are largely absent, harbor an unknown number of individuals with Chagas, probably infected decades ago. The article discusses major strides in Chagas disease knowledge and control, besides identifying persistent gaps, such as the need for housing improvements, especially in poor rural areas in the Americas.