The town began in 1900, when the Rock Island Railroad survey marked the site as a future station. The railroad ran along the Ozark Trail, which later became Route 66, creating an economic boom for this tiny agricultural community for decades until I-40 bypassed the town.

Adrian is the geo-mathematical midpoint of Route 66, and the town's motto is: "When you're here, you're halfway there." Today, travelers from all over the world take their photo in front of the sign that reads, "1,139 miles to Chicago–1,139 miles to Los Angeles."

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