- Craig Virgin, American Distance Runner
- Josephine Baker, East St. Louis, performer and activist
- Jason Boyd, Edwardsville, AAA pitcher
- Jimmy Connors, East St. Louis and Belleville, world-famous tennis player
- Brian Daubach, Belleville, former MLB 1B/DH/Outfielder
- Miles Davis, East St. Louis and Alton, world-famous jazz artist
- Elizabeth Donald, Edwardsville, horror novelist
- Buddy Ebsen, Belleville, Television Actor
- Jay Farrar, Belleville, musician
- Norm Greenberg, Belleville, Metro-East television personality
- Louis Jolliet, explorer of the Mississippi River
- Jackie Joyner-Kersee East St. Louis, World famous Olympic athlete
- Ken Kwapis Belleville, Film/Television director and producer
- Mark Little, Edwardsville, AAA outfielder
- Père Jacques Marquette, French discoverer
- Laurie Metcalf, Edwardsville, Film/Television actress (Rosanne, Uncle Buck, JFK)
- Yadier Molina, Caseyville, Cardinals Baseball Catcher (Resides there only during baseball season, and is originally from Puerto Rico)
- Peter Sarsgaard, Belleville/Scott AFB, Actor (Flightplan, Jarhead, Green Lantern)
- Jeff Tweedy, Belleville, lead singer of the band Wilco
- Uncle Tupelo, Belleville, alternative country band
- Robert Pershing Wadlow, Alton, World's Tallest Man
- William Holden, O'Fallon, Hollywood actor
- Michael Stipe, Collinsville, lead singer of the band REM
- Senator Richard J. Durbin, East St. Louis, U.S. senator
- T. J. Mathews, Columbia, former MLB pitcher
- Neal Cotts, Lebanon, Pitcher currently playing for the Chicago Cubs
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