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Current global agricultural production must feed over 7 billion people. However, productivity varies greatly across the globe and is under threat from both increased competitions for land and climate change and associated environmental deterioration. Moreover, the increase in human population size and dietary changes are putting an ever greater burden on agriculture. The majority of this burden is met by the cultivation of a very small number of species, largely in locations that differ from their origin of domestication. Recent technological advances have raised the possibility of de novo domestication of wild plants as a viable solution for designing ideal crops while maintaining food security and a more sustainable low-input agriculture. Here we discuss how the discovery of multiple key domestication genes alongside the development of technologies for accurate manipulation of several target genes simultaneously renders de novo domestication a route toward crops for the future.