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  1. Nitrogen (N) is an essential but generally limiting nutrient for biological systems. Development of the Haber-Bosch industrial process for ammonia synthesis helped to relieve N limitation of agricultural production, fueling the Green Revolution and reducing hunger. However, the massive use of industrial N fertilizer has doubled the N moving through the global N cycle with dramatic environmental consequences that threaten planetary health. Thus, there is an urgent need to reduce losses of reactive N from agriculture, while ensuring sufficient N inputs for food security. Here we review current knowledge related to N use efficiency (NUE) in agriculture and identify researchmore »opportunities in the areas of agronomy, plant breeding, biological N fixation (BNF), soil N cycling, and modeling to achieve responsible, sustainable use of N in agriculture. Amongst these opportunities, improved agricultural practices that synchronize crop N demand with soil N availability are low-hanging fruit. Crop breeding that targets root and shoot physiological processes will likely increase N uptake and utilization of soil N, while breeding for BNF effectiveness in legumes will enhance overall system NUE. Likewise, engineering of novel N-fixing symbioses in non-legumes could reduce the need for chemical fertilizers in agroecosystems but is a much longer-term goal. The use of simulation modeling to conceptualize the complex, interwoven processes that affect agroecosystem NUE, along with multi-objective optimization, will also accelerate NUE gains.« less