Chagas disease is a complex parasitic zoonosis that still threatens public health across the Americas. Initiatives to control transmission blood transfusion and non-native triatomine-bug vectors have yielded crucial advances; native vectors, however, actively bridge wild and domestic/peri-domestic transmission cycles throughout the region, and tens of thousands of people become infected each year. Oral-transmission outbreaks, urbanisation, and vertical transmission are additional/emerging issues calling for innovative strategic thinking. While critical for advocacy and sustained public health action, assessing Chagas disease burden remains difficult; the often-asymptomatic nature of infection, healthcare access limitations, pervasive underreporting, and other methodological hurdles inherent to reliably measuring incidence, prevalence, and disease progression all contribute to the difficulty. Whether and how parasite, vector, and host genetic makeups affect transmission dynamics and epidemiology is also unclear. Continued high-quality research and long-term, adaptive strategies combining vector control surveillance with enhanced case detection and integral patient care remain critical to effectively address the ethical and societal challenge of Chagas disease control. This is the first in a of five papers about Chagas Disease. All papers in the Series are available at https://www.thelancet.com/series/chagasdisease.