The Klamath River rises in the southeastern part of the U.S. state of Oregon, and flows about 263 miles (423 km) southwest through California, cutting through the southern Cascade Range to empty into the Pacific Ocean. The river drains an extensive watershed of over 15,000 square miles (39,000 km2) that stretches from the high desert country of the Great Basin to the temperate rainforest of the Pacific coast. It is known for its basin's peculiar geography—most of its upper basin is developed, but the lower remains wild—and has been called "a river upside down" by the National Geographic Society.

One of the most important anadromous fish rivers on the west coast of North America south of the Columbia River, the Klamath River basin has been inhabited by humans for at least 7,000 years. Once, the river supported abundant wildlife and vast freshwater marshes in the upper basin provided habitat for thousands of migratory birds. The first Europeans to visit the region were fur trappers for the Hudson's Bay Company in the 1820s, who established the Siskiyou Trail along the Klamath and Trinity Rivers into the Sacramento Valley. The latter days of the California Gold Rush saw increasing numbers of miners working streams in the Klamath River region in search of gold. Steamboats operated briefly on the large lakes in the upper watershed before the establishment of agriculture in the 19th and 20th centuries. The growing industry in the upper basin led to the construction of many dams on the river, which have since caused water quality issues for the lower river. The dams have caused petitions against the construction of further dams, and to remove the existing ones.

Because the Klamath includes many of the longest free-flowing stretches of river in California as well as some of its better whitewater runs, it has become a popular recreational river. Its watershed includes large swathes of the Klamath National Forest and Six Rivers National Forest. However, time and again, the Klamath has been targeted as a potential water source because of its generous flow, a rarity in most of California. For now, the lower Klamath remains undeveloped, although massive diversions were once proposed to reroute the river into the Central Valley to supplement the region's water supply.

Upper Klamath Lake, filling a broad valley at the foot of the eastern slope of the southern High Cascades, is considered the birthplace of the Klamath River. Its headstreams, however, begin over 100 miles (160 km) away—as far as Crater Lake and the Oregon-Nevada border. The first 1-mile (1.6 km) stretch of the Klamath River is known as the Link River. Not long after, however, the river is impounded in a 18-mile (29 km)-long reservoir near Klamath Falls, Lake Ewauna, where it receives the Lost River and passes the nearly-dry bed of Lower Klamath Lake. Even after it flows out of this reservoir, it drops through a series of three more artificial lakes before it crosses the Oregon-California state border and turns south near the town of Hornbrook towards the direction of Mount Shasta. However, the river soon swings west to receive the Shasta River and Scott River, cutting deep into the head of its canyon through the Klamath Mountain.

The route through the High and Western Cascades and the Klamath Mountains constitutes the majority of the river's course and takes it from the arid high desert climate of its upper watershed into a temperate rainforest nourished by Pacific rains. From the Scott River confluence, the river generally runs west until it takes a sharp southward turn near the town of Happy Camp. There, it flows southwest over whitewater rapids into the Klamath National Forest, receiving the Salmon River, and passing the unincorporated town of Orleans. At Weitchpec the river reaches the southernmost point in its entire course and veers sharply northwards as it receives the Trinity River. The Trinity River confluence also marks the point where the current of the Klamath slows down dramatically. For the remainder of its course, it flows generally northwest through the Hoopa Valley and Yurok Indian Reservations, passing the town of Klamath and flowing out to sea 16 miles (26 km) south of Crescent City.

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