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Some of the theatres that have developed and performed his works include New York’s Public Theater, New York Theatre Workshop, Pasadena Playhouse, McCarter Theatre, Oregon Shakespeare Festival, South Coast Repertory, The Alliance, New Theatre, Florida Stage and the Coconut Grove Playhouse.

Cruz's most recent work is Bathing in Moonlight, a world premiere featuring Raul Mendez, Priscilla Lopez, Hannia Guillen, Frankie J. Alvarez, Michael Rudko, and Katty Velasquez. Directed by Emily Mann (it has incorrectly been stated that Emily Mann directed the world premiere of Anna in the Tropics, the world premiere was directed by Rafael de Acha, artistic director of New Theatre, in Coral Gables, Florida. The following year, after being awarded the Pulitzer and Steinberg Awards, Emily Mann directed a production at the McCarter Theatre, which then was presented on Broadway.) Bathing in Moonlight ran September 9 - October 9, 2016, at McCarter Theatre in Princeton, New Jersey. Bathing in Moonlight is the recipient of an Edgerton Foundation New Play Award and a 2016 Greenfield Prize.

Cruz penned the libretto to composer Jimmy López's opera Bel Canto which had its world premiere at the Lyric Opera of Chicago on December 7, 2015.

Cruz is a frequent collaborator with Peruvian-American Latin Grammy composer Gabriela Lena Frank. To date, they have completed a set of orchestral songs, La centinela y la paloma (The Keeper and the Dove), for soprano Dawn Upshaw and the St. Paul Chamber Orchestra (premiered under the baton of Joana Carneiro in February 2011); The Saint Maker for soprano Jessica Rivera, mezzo-soprano Rachel Calloway, the San Francisco Girls Chorus, and the Berkeley Symphony in May 2013; and Journey of the Shadow for narrator and ensemble of eleven players (San Francisco Chamber Orchestra premiering in April 2013.

Cruz wrote the book of the Frank Wildhorn-Jack Murphy musical Havana. Its scheduled world premiere at the Pasadena Playhouse has been delayed by the theatre's declaration of bankruptcy in 2010.

In 2010, Cruz was awarded the honorary Doctor of Humane Letters (L.H.D.) from Whittier College.

In 2009, Cruz received the PEN/Laura Pels International Foundation for Theater Award for a distinguished American playwright in mid-career.

In 2001, Cruz served as the playwright-in-residence for the New Theatre in Coral Gables, Florida, where he wrote Anna in the Tropics. Rafael de Acha, produced and directed the world premier performance of Anna in the Tropics, winner of the 2003 Pulitzer and the Steinberg Award for Best New Play. A year later it received its Broadway premiere with Jimmy Smits in the lead role.

Cruz was born to Tina and Nilo Cruz, Sr. in Matanzas, Cuba. The family immigrated to Little Havana in Miami, Florida, in 1970 on a Freedom Flight, and eventually naturalised to the United States. His interest in theater began with acting and directing in the early 1980s. He studied theater first at Miami-Dade Community College, later moving to New York City, where Cruz studied under fellow Cuban María Irene Fornés. Fornes recommended Cruz to Paula Vogel who was teaching at Brown University where he would later receive his M.F.A. in 1994. Cruz is openly gay.

Nilo Cruz (born 1960) is a Cuban-American playwright and pedagogue. With his award of the 2003 Pulitzer Prize for Drama for his play Anna in the Tropics, he became the first Latino so honored.