The global challenge of meeting increased food demand and protecting environmental quality will be won or lost in cropping systems that produce maize, rice, and wheat. Achieving synchrony between N supply and crop demand without excess or deficiency is the key to optimizing trade-offs amongst yield, profit, and environmental protection in both large-scale systems in developed countries and small-scale systems in developing countries. Setting the research agenda and developing effective policies to meet this challenge requires quantitative understanding of current levels of N-use efficiency and losses in these systems, the biophysical controls on these factors, and the economic returns from adoption of improved management practices. Although advances in basic biology, ecology, and biogeochemistry can provide answers, the magnitude of the scientific challenge should not be underestimated because it becomes increasingly difficult to control the fate of N in cropping systems that must sustain yield increases on the world's limited supply of productive farm land.