Known informally as the CAM St. Louis, the museum is located at 3750 Washington Boulevard in the Grand Center Arts District.

It has exhibited work by Richard Aldrich, Laylah Ali, Lutz Bacher, Rosa Barba, Leslie Hewitt, Hayv Kahraman, Wyatt Kahn, Elad Lassry, Marilyn Minter, Gedi Sibony, Carey Young, Richard Artschwager, Jim Hodges, Sean Landers, Cindy Sherman, Arcangelo Sassolino, and Amy Sherald.

In 2016, Jefferey Uslip resigned from the chief curator position at the Contemporary Art Museum St. Louis due to criticism about a controversial exhibition.

The ongoing criticism of Kelley Walker's seemingly racially insensitive exhibit "Direct Drive" caused more than twenty artists to withdraw from the Contemporary Art Museum St. Louis's annual open studio tour.

The architects came up with a plan to create a space that is able to convey its own energy and calm feelings.