If current trends in human population growth and food consumption continue, crop production will need to substantially increase by mid-century to meet food demands and reduce hunger. A collaboration of crop modelers, physiologists, geneticists, plant breeders, and system agronomists is proposed to efficiently create genetic improvements that when taken to the field will have regional and global yield impacts. As an example, improving radiation use efficiency (RUE) is one of promising avenues to substantially increase potential yields. Improving RUE will require a large, internationally integrated science project and related infrastructure such as was recently developed in the Wheat Initiative. The Wheat Initiative is “a framework to establish strategic research and organizational priorities for international wheat research in both developed and developing countries” to sustainably improve global wheat production (www.wheatinitiative.org). The roadblocks to yield gains in challenging environments often include simultaneously improving resource use efficiency, developing sustainable wheat cropping systems, and maintaining grain quality for human consumption. The multidisciplinary expertise within the Expert Working Groups (EWGs) of the Wheat Initiative could be built around crop models that address a specific biological challenge of global significance. The power of crop simulation modeling has been recently enhanced through the establishment of a multi-model and internationally distributed simulation capacity within AgMIP-Wheat (https://www.agmip.org/ wheat/), as part of the Agricultural Model Intercomparison and Improvement Project (http://www.agmip.org/). The outcome of this proposed crop-model-driven, trait-focused collaborative research activity has the potential to improve wheat yields across the world to secure the increasing demand for food in the future. Using one trait as an example, genetic improvements will be linked to the field, and to regional and global yield impacts. Protocols and data exchange procedures should be applicable to explore other traits and trait combinations. The proposed integrated research is applicable to explore other traits and trait combinations and could become a model for yield improvements for major food crops.