In 1980, LaChiusa came to New York City, where he took gigs as a music director and accompanist while trying to find songwriting work. In the mid-1980s, he joined the BMI Lehman Engel Musical Theater Workshop, where he was strongly influenced by a series of mentors; at BMI, he segued from writing "camp" songs to more serious work. In 1993, The Public Theater's producer George C. Wolfe presented LaChiusa's First Lady Suite. A year later, Lincoln Center produced his musical Hello Again Off Broadway. A series of interconnected stories about love based on Arthur Schnitzler's play La Ronde, Hello Again was nominated for ten Drama Desk Awards, including three (Outstanding Book of a Musical, Outstanding Music, and Outstanding Lyrics) for LaChiusa.
In 1995, LaChiusa wrote additional book material for the Broadway musical Chronicle of a Death Foretold (an adaptation of Gabriel García Márquez's 1981 novella of the same name.) For the book, written with Graciela Daniele and Jim Davis, LaChiusa received a Tony Award nomination for Best Book of a Musical.
During the 1999-2000 season, LaChiusa had two large-scale musicals premiere on Broadway: Marie Christine and The Wild Party. Marie Christine, a retelling of the Medea myth set in 19th-century Louisiana, starred Audra McDonald and attracted controversy due to its grim subject matter and demanding score—The New York Times reported that "even the formidable and classically trained McDonald could sing it only six times a week, rather than the standard eight." Marie Christine closed after 42 performances; LaChiusa later said that the show "in my mind should have been performed for three performances[...]Only three. It's huge, and it's intensely difficult". The Wild Party was based on the 1928 poem of the same name by Joseph Moncure March, and starred Toni Collette, Mandy Patinkin, and Eartha Kitt. The Wild Party struggled commercially; after receiving seven Tony nominations but failing to win a single one, producers closed the show. For both Marie Christine and The Wild Party, LaChiusa received Tony nominations for Best Book of a Musical and Best Original Score.
In 2003, Little Fish, an uncharacteristically cheerful one-act musical of LaChiusa's based on two short stories by Deborah Eisenberg, premiered Off Broadway. The show's failure sent LaChiusa into a funk; he recalled, "I went, 'My God, they don't want the hard stuff and more challenging material here in this city from me. They don't want something nice and fun, either. What am I supposed to do?'"
In August 2005, LaChiusa published an article in Opera News that disparaged several successful, upbeat Broadway musicals of the 2000s, among them The Producers and Hairspray, which LaChiusa dubbed a "faux-musical". He continued, "Instead of choreography, there is dancing. Instead of crafted songwriting, there is tune-positioning. Faux-musicals are mechanical; they have to be. For expectations to be met, there can be no room for risk, derring-do or innovation." The article provoked shocked responses from several of LaChiusa's colleagues, who saw it as an attack.
In Fall 2005, LaChiusa's show See What I Wanna See, based on the stories "In a Grove," "The Dragon," and "Kesa and Morito" by Ryūnosuke Akutagawa, had a successful Off Broadway run at the Public Theater. For the show, LaChiusa was nominated for Drama Desk Awards for Outstanding Music and Outstanding Lyrics.
In September 2008, he was quoted in Opera News Online as working on an adaptation of Bizet's opera Carmen with Tony winner Audra McDonald in mind.
In April 2009, the Signature Theatre Company will premiere Giant, a musical adaptation of Edna Ferber's 1952 novel of the same name with music and lyrics by LaChiusa and book by Sybille Pearson, who wrote the book for the 1983 musical Baby (musical).
LaChiusa is an adjunct professor at the Graduate Musical Theatre Writing Program at the Tisch School of the Arts at New York University.
Bella, Belle of Bylorussia, book and lyrics by Jeffrey Essmann (1992)