Plant domestication is a coevolutionary process in which plants are selected to make them more useful to humans and adapted to the environment created by humans, while at the same time becoming less adapted to their original habitat in nature. This process is often considered to be related to the origins of agriculture, which occurred later but simultaneously in several regions of the earth, including the Neotropics. However, plant domestication in the Neotropics occurred within agroecological systems that focused on individual plants rather than populations, as is typical of agriculture. In this chapter we define the concepts of population domestication and landscape domestication, as well as different levels of plant population domestication, such as incidentally co-evolved, incipiently domesticated, semi-domesticated, and domesticated plants, and centers of domestication, including single and multiple independent centers of plant domestication in this part of the American continent. We examined the roles of archaeology, archaeobotany, paleobiolinguistics, genetics and genomics, and ethnobotany for a greater understanding of plant domestication in the Neotropics. We also define the concepts of domestication syndromes, genetic drift, selection signatures, among others, related to domestication in the Neotropics. Numerous plant species were domesticated in the Neotropics, such as Capsicum spp., Manihot esculenta, Theobroma spp., Phaseolus spp., Bertholletia excelsa, Annona cherimola, Bixa orellana, Cucurbita spp., among others, and case studies were presented for Ananas comosus, Zea mays, Solanum lycopersicum and Bactris gasipaes. Finally, we present future directions in the study of plant domestication in the Neotropics.