The South Platte River Basin was one of 20 study units selected in 1991 for investigation under the U.S. Geological Survey's National Water-Quality Assessment (NAWQA) program. One of the initial tasks undertaken by the study unit team was to review the environmental setting of the basin and assemble ancillary data on natural and anthropogenic factors in the basin. The physical, chemical, and biological quality of the water in the South Platte River Basin is explicitly tied to its environmental setting. The resulting water quality is the product of the natural conditions and human factors that make up the environmental setting of the basin.This description of the environmental setting of the South Platte River Basin and its implications to the water quality will help guide the design of the South Platte NAWQA study. Natural conditions such as physiography, climate, geology, and soils affect the ambient water quality while anthropogenic factors such as water use, population, land use and water-management practices can have a pronounced effect on water quality in the basin. The relative effects of mining, urban, and agricultural land-and water-uses on water-quality constituents are not well understood. The interrelation of the surface-water and ground-water systems and the chemical and biological processes that affect the transport of constituents needs to be addressed. Interactions between biological communities and the water resources also should be considered. The NAWQA program and the South Platte River Basin study will provide information to minimize existing knowledge gaps, so that we may better understand the effect these natural conditions and human factors have on the water-quality conditions in the basin, now and in the future. (KEY TERMS: South Platte River; water quality; water use; land use; water management; ecology.)