[2][1] Under the direction of Georgetown's Donn B. Murphy, his play The Toadstool Boy, about a country singer's quest for fame, won first place in the District of Columbia Recreation Department's One-Act-Play competition.

Guare's early plays, mostly comic one-acts exhibiting a flair for the absurd, include To Wally Pantoni, We Leave a Credenza, produced at Caffe Cino in 1965[2] and Muzeeka (1968).

[4][5] The House of Blue Leaves, a domestic drama by turns wildly comic and despairingly poignant, premiered Off-Broadway in 1971 at the Truck and Warehouse Theatre.

[11] Later plays include Marco Polo Sings a Solo, produced at the Joseph Papp Public Theater/New York Shakespeare Festival in January to March 1977, with a cast that featured Joel Grey, Anne Jackson, Madeline Kahn, and Sigourney Weaver.

[17] Six Degrees of Separation is an intricately plotted comedy of manners about an African-American confidence man who poses as the son of film star Sidney Poitier.

[18] Four Baboons Adoring the Sun was presented on Broadway at the Vivian Beaumont Theater from February 22, 1992, to April 19, 1992, and was nominated for the 1992 Tony Award, Best Play.

A Few Stout Individuals is set in nineteenth century America, with a cast of characters that includes Ulysses S. Grant, Mark Twain, soprano Adelina Patti and the Emperor and Empress of Japan.

[21] Guare wrote narration for Psyche, a tone poem by César Franck, which premiered at Avery Fisher Hall in October 1997, conducted by Kurt Masur with the New York Philharmonic.

[26] He was an original member in 1965 of the Eugene O'Neill Theater Center in Waterford, Connecticut[27] and Resident Playwright at the New York Shakespeare Festival, during which time he wrote Landscape of the Body, Rich and Famous, and Marco Polo Sings a Solo.

[30] He co-produces the New Plays Reading Room Series at the Lincoln Center Library for the Performing Arts and teaches in the Playwriting department at the Yale School of Drama.