De novo domestication is a novel trend in plant genetics, where traits of wild or semi-wild species are changed by the use of modern precision breeding techniques so that they conform to modern cultivation. Out of more than 300,000 wild plant species, only a few were fully domesticated by humans in prehistory. Moreover, out of these few domesticated species, less than 10 species dominate world agricultural production by more than 80% today. Much of this limited diversity of crop exploitation by modern humans was defined early in prehistory at the emergence of sedentary agro-pastoral cultures that limited the number of crops evolving a favorable domestication syndrome. However, modern plant genetics have revealed the roadmaps of genetic changes that led to these domestication traits. Based on such observations, plant scientists are now taking steps towards using modern breeding technologies to explore the potential of de novo domestication of plant species that were neglected in the past. We suggest here that in this process of de novo domestication, the study of Late Paleolithic/Late Archaic and Early Neolithic/Early Formative exploration of wild plants and identification of neglected species can help identify the barriers towards domestication. Modern breeding technologies may then assist us to break these barriers in order to perform de novo domestication to increase the crop species diversity of modern agriculture.