Cereal production that now sustains a world population of more than 6.5 billion has tripled during the past 40 yr, concurrent with an increase from 12 to 104 Tg yr(-1) of synthetic N applied largely in ammoniacal fertilizers. These fertilizers have been managed as a cost-effective form of insurance against low yields, without regard to the inherent effect of mineral N in promoting microbial C utilization. Such an effect is consistent with a net loss of soil organic C recently observed for the Morrow Plots, America's oldest experiment field, after 40 to 50 yr of synthetic N fertilization that substantially exceeded grain N removal. A similar decline in total soil N is reported herein for the same site and would be expected from the predominantly organic occurrence of soil N. This decline is in agreement with numerous long-term baseline data sets from chemical-based cropping systems involving a wide variety of soils, geographic regions, and tillage practices. The loss of organic N decreases soil productivity and the agronomic efficiency (kg grain kg(-1) N) of fertilizer N and has been implicated in widespread reports of yield stagnation or even decline for grain production in Asia. A major global evaluation of current cereal production systems should be undertaken, with a view toward using scientific and technological advances to increase input efficiencies. As one aspect of this strategy, the input of ammoniacal N should be more accurately matched to crop N requirement. Long-term sustainability may require agricultural diversification involving a gradual transition from intensive synthetic N inputs to legume-based crop rotations.