Halsey C. Ives was the museum's first director, and during his tenure, the collection focused on contemporary American artists, notably William Merritt Chase.

In that year, the City Museum of Art was formed, and began to acquire its own artwork funded from a unique civic tax levy, separately from the private university collection.

Janson's plan to sell popular canvases such as Frederic Remington's A Dash for the Timber at the New York galleries of the Kende family drew comment from the local paper, wondering why St. Louisans had not been given preference.

[7] Janson sold 120 artworks, retained 80, and acquired 40 works by European modernists through the Kende Galleries:[8] Paul Klee, Juan Gris, Theo van Doesburg.

Recently, the museum has continued to focus on the acquisition of contemporary works, including pieces by Jackson Pollock, Robert Rauschenberg and Jenny Holzer.

The museum's Florence Steinberg-Weil Sculpture Garden was relocated to a setting north of the Sam Fox School's new Anabeth and John Weil Hall.

[10] In September 2019, the newly expanded and renovated Mildred Lane Kemper Art Museum opened with a major exhibition of work by Ai Weiwei: "Bare Life".

The Sam Fox School is dedicated to the creation, study, and exhibition of multidisciplinary and collaborative work with an emphasis on fostering creativity and intellectual exchange.

The permanent collection of the museum, exhibited on its top floor and within the Florence Steinberg Weil Sculpture Garden, includes extensive representation by 19th, 20th and 21st Century works.

The museum is curated by Tom Serfass and also features items documenting Benjamin Franklin's role as a figure of early American Colonial paper money.