The well-documented decline of water quantity and quality in the High Plains (or “Ogallala”) aquifer is a direct result of the inextricable link between human existence and its reliance on water from the aquifer. The High Plains aquifer underlies about 450,700 km2 in the semi-arid west-central United States (US) and is one of the largest freshwater aquifers in the world. The aquifer is critically important for US agriculture, supporting about 27 percent of the irrigated land in the US, and supplying about 30 percent of all the ground water used for irrigation in the US. Human-induced stresses on ground water, in the form of increasingly large withdrawals for irrigated agriculture since the 1950s, have resulted in water-table declines greater than 30 meters in some areas. Aquifer depletions are affecting well production rates, streamflow, and ecosystem health, and are increasing agricultural production costs. Ground-water quality has been impaired from head reversals at the base of the aquifer that allow upward percolation of saline water, and from the application of agricultural chemicals and irrigation water at the land surface, which has led to widespread nitrate and pesticide contamination. In addition, natural climate variability and possible climate change will affect precipitation, evapotranspiration, soil-moisture retention, aquifer recharge, and chemical transport, and will have important implications for management of ground-water resources. These problems raise questions about aquifer sustainability, the future of the agricultural industry, ecosystem health, water availability, and water quality concerns for nearly 2 million people who rely on the aquifer as a source of drinking water. This presentation outlines the historical development of life related to water use on the US High Plains and how the reliance on water from the aquifer has prompted questions of resource sustainability. In addition, the High Plains human-water system will be presented in terms of on-going national and international studies to better understand these dynamic and interactive relations, and will highlight efforts to provide the best available science that supports successful management and sustainability of this important resource.