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The setting for the fictional town of Radiator Springs is situated between Gallup, New Mexico and the Sonoran Desert in California. However, the physical location of Radiator Springs in relation to I-40 is similar to that of Peach Springs, Arizona.

Lasseter told film critic Joe Williams of the St. Louis Post-Dispatch that much of the story is based on the recollections of barber Angel Delgadillo in the Route 66 town of Seligman, Arizona, where business withered soon after the opening of I-40.

Willy's Butte resembles the landmark of Mexican Hat, Utah, but also resembles a classic Pontiac hood ornament.

There is an "Ornament Valley" (a reference to Monument Valley).

The epilogue shows a map of the area of Arizona around Radiator Springs, including car-related place names such as "Carburetor County" and "Cadillac Range". The latter is a large north-to-south mountain range with many fin-backed jagged peaks, a reference to the famous Cadillac Ranch sculpture in Amarillo, Texas. Where the main road crosses the Cadillac Range is marked "Tailfin Pass 5942" (i.e. feet altitude, = 1.8111 kilometers).

Lizzie's Curio Shop in Radiator Springs resembles the crazy Route 66 jumble of memorabilia and knick-knacks at Hackberry General Store in Hackberry, Arizona and the Sand Hills Curiosity Shop, aka the City Meat Market building in Erick, Oklahoma.

The bridge that McQueen sees Sally driving on resembles several bridges on Route 66, including the Cyrus Avery Route 66 Memorial Bridge in Tulsa, the Colorado Street Bridge in Pasadena, California, and the now-closed bridge over Diablo Canyon at Two Guns, Arizona.

Flo's V8 Cafe is designed to look like a V8 engine head on, with a circular air filter, tappet covers, spark plugs, pistons and connecting rods as the supports for the shelter. The blinking neon lights on the spark plugs blink in the firing order of a Ford flathead V8.

The railroad grade crossing at which Lightning McQueen outruns a passenger train on his way to Radiator Springs is protected by a pair of antique "upper-quadrant" wigwag crossing signals which accurately depict those once made by the Magnetic Signal Company in both appearance and start-up. Few are left in actual operation in the United States, and many have been replaced with modern crossing gates, red lights and bells.

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