Water quality of the High Plains aquifer was assessed for the period 1999-2004 as part of the U.S. Geological Survey's National Water-Quality Assessment (NAWQA) Program. This effort represents the first systematic regional assessment of water quality in this nationally important aquifer. A stratified, nested group of studies was designed to assess linkages between the quality of water recharging the aquifer, the effect of transport through the hydrologic system on water quality, and the quality of the resource used for human consumption and agricultural applications. The stratified, nested design facilitated upscaling of monitoring results to unmonitored areas of the aquifer as well as upscaling of process understanding from local to regional scales.