The Green Revolution of the 1960s improved crop yields in part through the widespread cultivation of semidwarf plant varieties, which resist lodging but require a high-nitrogen (N) fertilizer input. Because environmentally degrading synthetic fertilizer use underlies current worldwide cereal yields, future agricultural sustainability demands enhanced N use efficiency (NUE). Here, we summarize the current understanding of how plants sense, uptake, and respond to N availability in the model plants that can be used to improve sustainable productivity in agriculture. Recent progress in unlocking the genetic basis of NUE within the broader context of plant systems biology has provided insights into the coordination of plant growth and nutrient assimilation and inspired the implementation of a new breeding strategy to cut fertilizer use in high-yield cereal crops. We conclude that identifying fresh targets for N sensing and response in crops would simultaneously enable improved grain productivity and NUE to launch a new Green Revolution and promote future food security.