Recent paleoecological, archaeobotanical and genetic-molecular data are used to develop a hypothesis on the where, when, how and whom of plant domestication and the origin of agriculture in west Mesoamerica, and the formation of the maizebean-squash multicrop milpa system and agro-food system which formed the base for development of ancient complex societies in this area. It is highly likely that about 10,000 before present (BP) human groups specializing in plant gathering and small game hunting in the dry tropical forest of the Balsas-Jalisco biotic morphotectonic province began the process of plant domestication and agriculture, using fire as a tool. Sympatric distribution of the putative wild ancestral populations of maize, beans and squash indicate the extreme northwest Balsas-Jalisco region as a possible locus of domestication. Diffusion of these domesticates to the rest of Mesoamerica would have occurred via existing biological-cultural corridors. The milpa agro-food system would have been established between 7,000 and 4,400 calendar years (cal) BP. The complex food technology developed in the northwest Balsas-Jalisco region between 4,500 and 3,500 BP, much more complex than in other areas at the time, also suggests this area as the origin of the milpa agro-food system. Further archaeobotanical research is needed to confirm this hypothesis. Exploratory, collection and conservation efforts are needed in these putative source populations, as well as studies on their adaptation to climatic, edaphic and biotic factors, before they are displaced by the African grasses and pesticides forming part of the region's growing cattle industry.