Bison restoration has profound implications for ecological, economic and cultural domains, especially restoration into their former historic ranges. Climate change and climate variability, however, threaten sustainable restoration progress. The historic range of bison centered on the prairies of the Great Plains but spanned from Alaska to Mexico and from the Pacific coast to Florida and Pennsylvania, land which is now primarily privately held. Today, 63% of the 184,000 privately owned bison are located in the northern Great Plains, with 12,000 additional bison in the public sector, and 20,000 additional bison in each of the non-profit NGO and Tribal sectors. This multi-sectoral production-conservation system is referred to as the bison management system (BMS) and all sectors are intricately and economically linked through the production market and the cross-transferal of surplus animals. Bison are native ecological keystone species in native prairies and help to restore ecosystems. Their innate wallowing behavior produces shallow bare-soil depressions which create habitat for many other prairie-inhabiting species. Because bison create these wallows by excavating, urinating, and rolling, they also open the seed bank and concentrate nutrient inputs, and in turn increase plant biodiversity in the immediately adjacent landscape. Economically, the bison market has grown over the past 20 years, with bison market returns 1.5–3.3 times that of cattle. Finally, bison repopulation on Tribal lands increases food sovereignty, enhances economic stability, and revitalizes cultural connections to Tribal lands. The newly established Center of Excellence for Bison Studies at South Dakota State University aims to advance research, education, and outreach that address issues associated with each the ecological, economic, and cultural domains throughout the BMS, and is especially focused on restoration challenges associated with climate change and climate variability in conservation and production settings.