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The Corvette was replaced every three thousand miles. Chevrolet was the show's sponsor. It was never explained how Tod was able to get a new Corvette so often.

One memorable episode featured Boris Karloff, Lon Chaney Jr., and Peter Lorre. Karloff and Chaney were given the chance to don their famous Universal Frankenstein Monster and Wolf Man make-up for the first time in a few decades.

Although the series was called "Route 66," many of the episodes were set in areas in the United States, through which Route 66 did not travel. For example, Route 66 begins in Chicago and ends in Los Angeles, or vice versa, but two episodes were shot in New England, one in Maine, season four,, episode two, "Same Picture, Different Frame", and one in Vermont, season four, episode three, "Come Out, Come Out, Wherever You Are". Both aired in the fall of 1963, and starred Martin Milner and Glenn Corbett.

The Corvette was never red, as often believed. It was light blue in the first season, beige in the second season, and tan in the third season. The colors were chosen because they photographed well in black and white.

According to Glenn Corbett, none of the episodes, in which he appeared, were shot along the real Route 66. When he asked the producers why, he was told the scenery along the actual highway was not considered interesting enough.