The past 200 years have seen the US Midwest be transformed from natural prairie/wetlands to the most fertile croplands that currently produce about one third of global corn and soybean. Such a landscape transformation by human activities through extensively subsurface tiling and intensified uses of fertilizer and other inputs has also created significant concerns in environmental sustainability. With further stress from climate change, could the US Midwest remain as the global food basket in the next 100 years? How can we ensure co-sustainability of food production and environmental quality in this landscape? Carbon (e.g. crop growth), hydrology (both water quantity and quality), and nutrient cycles are closely intertwined in this landscape from the field/headwater scale to the whole river network and continental scales. Any human activities and practices do not singly affect one component, but the whole interconnections. Their complex feedbacks and non-linear interactions require a “system” view when assessing the US Midwest landscape and the potential adaptations. This talk will discuss how we adopt a “system” view to holistically model and quantify the coupled “food-water-nutrient nexus” for the US Midwest agroecosystems, aiming to significantly advance the process-based understanding and predictability of this agroecosystem under current and future climate conditions, with assessments of various promising management practices (e.g. cover crop, controlled drainage, and nutrient management) to achieve cosustainability of food production and environmental quality.