The play premiered at the Globe Theatre in Spring 1606. It was performed by the King's Men, but casting is uncertain. John Lowin may have performed the title role, as he is associated with the role in James Wright's Historia Histrionica (1699). William Gifford hypothesized that Alexander Cooke may have played Lady Would-be. Either that summer or the next, an outbreak of plague closed the London theatres, and the company performed the play at Oxford and Cambridge. Jonson may have added the first act's satire on Pythagoras for these audiences. The play certainly remained in the King's Men's repertoire throughout the period. It was performed for Charles in 1624 while he was still Prince of Wales, in 1630, and again at the Cockpit-in-Court in 1637.

After the Restoration, the play enjoyed a lengthy prominence: John Genest records over fifty performances before 1770. John Evelyn saw it performed at the court of Charles II on 16 October 1662. When the theatres reopened, the play was owned by the King's Men of Thomas Killigrew; it was performed at Drury Lane in 1663. Michael Mohun played Volpone to Hart's Mosca; Katherine Corey played Celia, and Rebecca Marshall played Lady Would-be. The same cast was seen by Samuel Pepys in 1665.

The play continued in performance throughout the 18th century. Richard Steele mentions a performance in a 1709 edition of Tatler. Famous eighteenth-century Volpones included James Quin; famous Moscas included Charles Macklin. Colley Cibber played Corvino in his productions; his wife Katherine Shore played Celia, as later did Elizabeth Inchbald. As with many other Jacobean plays, Volpone had lost its appeal before the end of the 18th century. Earlier in the century, critics had complained about the improbability of the fifth act, frequently likened to farce, and to Jonson's highly Latinate language. An updated version by George Colman the Elder failed at Drury Lane in 1771. By the end of the century, the objections appeared insurmountable to producers, and the play fell into disuse.

The play was revived by the Phoenix Society at the Lyric Hammersmith in 1921; W. B. Yeats was in the audience and mentions the production approvingly in a letter to Allan Wade. The Birmingham Repertory Theatre staged the play at the Malvern Festival in 1935.

A 1938 production introduced two of the dominant elements of twentieth-century productions: the performance of Donald Wolfit and animal imagery. Wolfit's dynamic performance in the title role, repeated several times over the next decades, set the standard for modern interpretations of Volpone: Politick's plot was truncated or eliminated, and Mosca (played in 1938 by Alan Wheatley) relegated to a secondary role.

The play has since been staged by a number of famous companies. In 1952, George Devine directed Anthony Quayle (Mosca) and Ralph Richardson (Volpone) at the Stratford Memorial Theatre. At the same theatre in 1955, Eric Porter played Volpone. In 1968, Tyrone Guthrie's National Theatre production emphasized the beast-fable motif; this production featured stage design by Tanya Moiseiwitsch.

In 1972, the play was staged at the Bristol Old Vic. A most memorable production of the 1970s was Peter Hall's staging for the Royal National Theatre in 1974, with Paul Scofield as Volpone, Ben Kingsley as Mosca, John Gielgud as Sir Politick, and Ian Charleson as Peregrine.

Matthew Warchus received an Olivier Award nomination for his 1995 production at the Royal National Theatre; it featured Michael Gambon and Simon Russell Beale.

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