Mellencamp wrote the song about his experiences growing up in a small town in Indiana, having been born in Seymour, Indiana, and living in Bloomington, Indiana, which, at the time of the release of the song, was much smaller. The music video has references to both towns. After that, Mellencamp has been known as champion of "small town America."
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NBA legend and fellow Indiana native Larry Bird used this song on his retirement ceremony in 1993, particularly referring his town French Lick, Indiana as a "small town". It was also used for him in the NBA Superstars video series.
The song was played in The Waterboy.
While performing for the NFL Kickoff Special on NBC on September 6, 2007 to celebrate his hometown Indianapolis Colts opening the season after winning Super Bowl XLI, some of the well-known lyrics were changed. "My wife was 13 when I wrote this song" being among the more humorous of lines not in the original. The "L.A. Doll" he sings of in the original version was his then-wife Victoria Granucci.
The song was used as the opening theme to the television movie, The Ryan White Story.
The song was also used as the theme song for the Discovery Times documentary series Off to War, which covered Arkansas Army National Guard soldiers, most of them from ruralClarksville, Arkansas, during their tour of duty in Operation: Iraqi Freedom.
The song is played after Green Bay Packers games.
For a while, it was performed by Paul Shaffer and the CBS Orchestra prior to and in closing the Small Town News sketches featured on Late Show with David Letterman.