[2] In 1970, under Director Betty Collings' leadership, the gallery began hosting major contemporary artists and acquiring the collection that would become the Wexner Center as a response to student grievances about the Kent State shootings.

[4] Peter Eisenman won the design competition for the Wexner in 1983 over four other, more experienced finalists: Cesar Pelli; Michael Graves; Kallmann McKinnell & Wood; and Arthur Erickson.

[5] The Wexner Center opened on November 17, 1989, and architects like Philip Johnson, Richard Meier and Charles Gwathmey convened in Columbus to mark the building's completion with a public forum on the state of American architecture.

"[5] During its three-year renovation between 2002 and 2005, the Wexner relocated its galleries in a former coffin factory two miles away, while the performing arts and film programs continued at the center.

Based on the controversial theory that art should be "challenged" by its environment rather than displayed neutrally, the museum raised Eisenman's profile and he went on to design and build a number of other major projects including the Memorial to the Murdered Jews of Europe in Berlin.

[7] The design includes a large, white metal grid meant to suggest scaffolding, to give the building a sense of incompleteness in tune with the architect's deconstructivist tastes.

[4][8] The center's brick turrets make reference to the Ohio State University Armory and Gymnasium, a castle-like building that occupied the site until 1958.

Notable exhibitions include: Chris Marker: Silent Movie, Julie Taymor: Playing With Fire, Shirin Neshat: Suite Fantastique, As Painting: Division and Displacement, Mood River, Pier Paolo Calzolari, Part Object Part Sculpture, Twice Untitled and Other Pictures (looking back), Louise Lawler, Chris Marker Staring Back, William Wegman: Funney/Strange, Andy Warhol: Other Voices, Other Rooms, and William Forsythe: Transfigurations.

Day; designs by Peter Eisenman, Kivi Sotamaa, and Ben van Berkel; and "products" like the Stealth Bomber and the Redman Self-Defense Instructor suits.

Creative residency and commissioning projects for artists include: Bill T. Jones, Anne Bogart and the SITI Company, Big Art Group, Ann Hamilton (in collaboration with Meg Stuart and subsequently with Meredith Monk), Improbable Theatre, Bebe Miller, The Builders Association, Akram Khan, Elizabeth Streb, Eiko & Koma, The Wooster Group, Savion Glover, Urban Bush Women, Anthony Davis, Richard Maxwell, da da kamera, Mark Morris, Young Jean Lee's Theater Company, and Kronos Quartet.

Residencies at the Wexner Center offer support to artists and often provide opportunities for interaction with the Ohio State community and the public at large.

Other artists participating in exhibitions and performances also may receive commissions and often engage in residency activities—workshops, master classes, and discussion sessions with students or the community—during their time at the center.

On March 4, 2022, staff at the Wexner Center for the Arts announced their intent to form a union with the American Federation of State, County and Municipal Employees (AFSCME).

[19] Wex Workers United sought, but were not granted, formal voluntary recognition of the union from leadership at the Ohio State University and the Wexner Center for the Arts.