Losses of nitrogen from agriculture are major threats to environmental and human health at local, regional, and global scales. Emerging evidence shows that climate change and intensive agricultural management will interact to increase these harmful effects and undermine current mitigation efforts. Identifying effective mitigation strategies and supporting policies requires an integrated understanding of the processes underlying potential agricultural N responses to climate change. In this review, we describe these processes, propose a set of multi-scale principles to guide research and policy for decreasing nitrogen losses in the future, and describe the economic factors that could constrain or enable their implementation.