In the 19th century the Clark Fork Valley was inhabited by the Flathead tribe of Native Americans. It was explored by Meriwether Lewis of the Lewis and Clark Expedition during the 1806 return trip from the Pacific. The river is named for William Clark. A middle segment of the river in Montana was formerly known as the Missoula River. The river was also referred to as the Deer Lodge River by Granville Stuart. David Thompson used the name Saleesh River for the entire Flathead-Clark Fork-Pend Oreille river system.

For most of the first half of the 19th century the Clark Fork river and surrounding region was controlled by the British-Canadian North West Company and Hudson's Bay Company. In the mid-19th Century the Clark Fork River wound through the valley where cattle had replaced bison. This was when Conrad Kohrs purchased a ranch from Johnny Grant that is now called the Grant-Kohrs Ranch.

Since the late 19th century many areas in the watershed of the river have been extensively mined for minerals, resulting in an ongoing stream pollution problem. Most pollution has come from the copper mines in Butte and the smelter in Anaconda. Many of the most polluted areas have been designated as Superfundsites. Nevertheless the river and its tributaries are among the most popular destinations for fly fishing in the United States.

Today, the Clark Fork watershed encompasses the largest Superfund site in America. As a mega-site, it includes three major sites: Butte, Anaconda, and Milltown Dam/Clark Fork River's Milltown Reservoir Superfund Site. Each of these major sites is split up into numerous sub-sites known as Operable Units. Remediation and/or restoration of these sites is ongoing.
https://en.wikipedia.org/wiki/Clark_Fork_River

In the early 1800s Native American tribes traveled through the area.  The fertile valley was used for wintering their ponies, harvesting salmon, and holding great councils. Mountain men, trappers, surveyors, and map makers were soon to follow. White settlers began their movement into the valley in the late 1860s.  During the decades to follow farming, ranching, and lumbering would flourish in the valley. The Northern Pacific Railway arrived in 1881-1883 and the town began to increase in size and importance.  Businesses flourished and eventually the name was shortened to Horse Plains and finally to Plains. 
http://www.waymarking.com/waymarks/WMKX68_Wild_Horse_Plains_Plains_MT