US 66 runs southwestward to the center of the state through mining districts and oil and gas fields, thence westward to the Texas Line through farming and stock country. Part of the route traverses the area visited by Washington Irving in 1832, when the land was a virgin wilderness. He related his adventures in A Tour on the Prairies, published in 1835. In 1916, the part of US 66 linking Oklahoma City with Amarillo was improved as a postal highway.

Toward the western end, as the highway rises gradually to higher elevations, the air seems to become clearer, towns are visible at great distances, and tall office buildings loom mirage-like above the level land. The region is aptly called the country of short grass and high plains.