Managing Nitrogen (N) is fundamental, yet challenging, for sustainable development: N is essential for producing crops and livestock and consequently important for food security. However, the rising N inputs from human activities to the biosphere has gone beyond a “planetary boundary for a safe operating space”, leading to severe environmental issues, ranging from local water and air pollution to global climate change. To address the N challenge, more N-efficient technologies in crop or livestock production alone are insufficient. A broader understanding of the complex trade-offs and responses of markets, governments, and consumers is needed. Here we present a hierarchical framework encompassing the complex cycles of N in human activities and natural systems, yet simple enough to guide policies and day-to-day actions: The Cropping system is nested within Animal-crop system, which is nested within the Food system, and finally nested within watershed Ecosystem (CAFE).