Nitrogen (N) emissions to ground and surface waters have become a major concern in many regions. In reaction, policy makers are tightening environmental constraints on agriculture, resulting in a call for more efficient management systems. This study presents a methodology for precision N fertilization in high-input farming systems applying split fertilizer strategies. Essentially, the method uses a mechanistic simulation model to quantify (i) soil mineral-N levels and (ii) N uptake rates on a real-time basis. Early warning signals are generated once N concentrations drop below a critical threshold level, indicating that additional fertilizer should be applied. Thresholds are not static, but defined in relation to actual uptake rates. Spatial variation is incorporated through the concept of management units: i.e., stable units with relatively homogeneous characteristics in terms of water regimes and nutrient dynamics. Separate simulations are conducted for each management unit, based on selected representative soil profiles. The proposed methodology was tested in a winter wheat (Triticum aestivum L.) field during the 1998 growing season. Six experimental strips were delineated receiving either ‘precise’ or traditional fertilization. Precision fertilization proved efficient in reducing fertilizer inputs (−23%), while slightly improving grain yields (+3%) and hectoliter weights (+4%). Results clearly illustrate the significance of precision management in the process of increasing fertilizer use efficiency.