The 2019 report of the Global Commission on Adaptation for accelerated action to adapt to climate change included a call for increased allocation of resources to international agricultural research. The production and adaptation challenges faced by agriculture will be most acutely felt in Africa and South Asia, focus regions of the CGIAR, the world’s largest public food systems research network. These challenges come at a time when the CGIAR is undergoing a transformation of its partnerships, knowledge, assets and global presence, emerging as One CGIAR, aimed at sharpening its mission and impact focus to 2030 and beyond, in line with the Sustainable Development Goals. Evidence on the impacts of CGIAR research since the 1980s have consistently found high rates of return to investment. How could this evidence on the performance of the CGIAR and its partnership with NARS in developing regions be used to inform investment priority setting and to achieve the One CGIAR goals in the coming years? We used detailed R&D investment data from the CGIAR, NARS (ASTI) and evidence from the literature on returns to CGIAR investment by crop and region to develop and calibrate a model of R&D investment that allows us to conduct priority-setting analysis of alternative CGIAR investment across research activities and regions. The model developed can be linked to global partial equilibrium and economy-wide forward-looking models to analyze the effect of different CGIAR investment options under alternative future scenarios. We checked the plausibility of the results obtained by the model calculating the Benefit-Cost ratio of historical CGIAR investments and found that each dollar invested by the CGIAR between 1971 and 2018 returned almost 10 dollars in output as the result of increased productivity, which is within the range of returns found by most recent meta-analyses impact of CGIAR investment. An application of the model to SSA shows that the best results for the CGIAR are obtained from investments in cassava and potato in Southern Africa; yams, sorghum, cassava and groundnuts in West Africa; cassava in East Africa and groundnuts and shoats in the Sahel.