The United States settlers and army fought with the Cherokee over land in Tennessee, North Carolina, and further South into Georgia and Alabama.

The North Fork flows 138 miles (222 km) southwest from Sharon Springs in Bland County, Virginia.

The Holston River valley has been greatly developed for electrical power generation, both with hydroelectric dams and coal-fired steam plants.

In the upper reaches, some of these plants are controlled by private interests; in the downstream portion, they are owned by the United States Government's Tennessee Valley Authority.

South Holston Lake offers a variety of fishing opportunity as well, as it contains smallmouth bass, common carp, walleye, pike, sunfish, crappie and a few trout.