John Heminge was paid twice for performances of a play called Cardenio by the King's Men at Greenwich Palace in 1613. In 1653 the stationer Humphrey Mosely registered his possession of a play called "The History of Cardenio by Mr. Fletcher and Shakespeare." In 1727 a play called The Double Falsehood was staged at Drury Lane and published as "Written originally by W. Shakespeare and now Revised and Adapted to the Stage by Mr. Theobald." Theobald claimed to have obtained a copy of Cardenio made by John Downes of the original script owned by the actor Thomas Betterton, which had been given by Shakespeare to "a natural daughter of his." Theobald mentioned opinion that the script might be mostly by Fletcher, and his version was not until recently thought to be Shakespearean. However, with the publication of Brean Hammond's Arden edition of the script opinion has become more sympathetic to its potential inclusion of some Shakespearean elements. Bernard Richards staged a version of it at the Edinburgh Festival in 2009, and Greg Doran developed a script for production at the RSC's Swan Theatre in 2011.

By contrast to the Theobald version, Charles Hamilton published an edition of Cardenio based on a manuscript in the British Library called The Second Maiden's Tragedy which he claimed to be in Shakespeare's handwriting, but which most scholars believe was composed by Thomas Middleton. Productions of this script have been staged at Oxford's Burton Taylor Theatre in March, 2004; at Essex University's Lakeside Theatre on October 15, 1998; on March 17, 1996, at the Linhart Theatre in New York; at the Next Theatre in Evanston Illinois in 1998; and by the Lone Star Ensemble at the 2100 Square Feet Theatre in Los Angeles in 2002.

The reconstituted version of the original script, created by Gregory Doran by drawing on the relevant episodes in Cervantes' Don Quixote, was indeed very successfully staged by the RSC at the Swan Theatre, Stratford-on-Avon in 2011 (for several online reviews, see the bibliography). A now largely lost play called Cardenio and associated with Shakespeare certainly once existed.