[5] Along the banks is a chain of cities and villages, including Oshkosh, Neenah, Menasha, Appleton, Little Chute, Kimberly, Combined Locks, and Kaukauna.

Since the recession of the glaciers that once covered much of Wisconsin, the Fox River has supported several Native American cultures, and has been important for its fisheries, waterfowl, wild rice, forests, and water.

[6] Prior to European settlement in the late 17th century, the shores of the Fox River and the Green Bay were home to roughly half the estimated 25,000 Native Americans who lived in what is today Wisconsin.

It was likely long used by Native Americans prior to European encounter, as they had extensive cross-country trading routes related to the Mississippi River.

French-Canadian men who established homes on the Fox River married First Nation women, producing mixed-race descendants who were generally raised within the matrilineal cultures of their mothers and identified with the tribes.

[7] The company was hoping to establish Green Bay as a port city to rival Chicago by making the Fox-Wisconsin Waterway into the principal shipping route between Lake Michigan and the Mississippi River.

[7] During the mid-19th century, when Wisconsin was a leading producer of wheat, several flour mills were built along the river to harness its abundant water power.

[citation needed] The principal cities located in this valley are Green Bay, Appleton, Neenah, Menasha, De Pere, and Kaukauna.

[12] The Fox River will continue to be monitored by the Environmental Protection Agency and Wisconsin Department of Natural Resources for many years following the cleaning project's completion.

Public debate about this contamination began as early as 1923, but little was done to improve the river until the federal Clean Water Act was passed in 1972.

According to some measures of pollution (e.g. dissolved oxygen, pollution-tolerant worm counts), the Lower Fox River is much cleaner than it was before 1972.

As a result, debate over the river's contamination continues between environmentalists, the paper industry, Indian tribes, and elected officials at the federal, state, and local levels.

While not officially designated as a U.S. Superfund site, the Lower Fox River bottom has some sections contaminated with toxic chemicals.

The Wisconsin Department of Natural Resources explains that carbonless copy paper caused PCB pollution in the Fox River and Lake Michigan.

[13] The U.S. government and State of Wisconsin filed suit on October 14, 2010, against nine paper companies and two municipalities for their failure to pay for PCB cleanup actions.

[14][15] Several settlements ensured that the responsible parties paid for a large sum of the cleaning project costs and other restoration efforts.

[18] Among the wildlife in the Fox River Valley are birds such as mallard ducks and Canada geese, and fish such as walleye.

[6] The Fox River region has been dominated by dairy farms that benefited from the rich soil and plentiful water supply.

The 25-mile (40 km) Fox River State Recreational Trail is part of the Brown County Park System.

[19] The Wiouwash State Trail runs concurrent with the Fox River from downtown Oshkosh to Lake Butte des Morts for about four miles (6.4 km).