Crops based on mixtures of species or genotypes support yield stability by providing multiple ecosystem services. However, the genetic, molecular, and evolutionary dynamics underlying co-adaptation within such mixtures must be understood to optimize beneficial plant-plant interactions. We therefore propose agroecological genomics as an integrated quantitative and population genetics approach that can be combined with cutting-edge omics methods and participatory science. This strategy embraces the heterogeneity of agroecosystems derived from interactions between biotic and physical environmental components such as climate, crop management, and socio-cultural factors by exploiting decentralized research. The integration of such results will reveal the whole-genome patterns of co-adaptation in crop mixtures, leading to greater knowledge of the key traits that drive adaptation as well as to the development of innovative tools for mixed-crop breeding.