Nitrous oxide (N2O) is often the largest single component of the greenhouse-gas budget of individual cropping systems, as well as for the US agricultural sector as a whole. Here, we highlight the factors that make mitigating N2O emissions from fertilized agroecosystems such a difficult challenge, and discuss how these factors limit the effectiveness of existing practices and therefore require new technologies and fresh ideas. Modification of the rate, source, placement, and/or timing of nitrogen fertilizer application has in some cases been an effective way to reduce N 2O emissions. However, the efficacy of existing approaches to reducing N2O emissions while maintaining crop yields across locations and growing seasons is uncertain because of the interaction of multiple factors that regulate several different N2O-producing processes in soil. Although these processes have been well studied, our understanding of key aspects and our ability to manage them to mitigate N2O emissions remain limited.