Skyler is the author of the play "The Moonlight Room", about at-risk youth in New York City, which she co-produced at the TriBeCa Playhouse in 2003 before transferring to a commercial run Off-Broadway on Theater Row. It was named one of the 'Ten Best Plays of the Year' by The New York Times and The New York Post, and has since been performed all over the country. Previously she co-wrote the feature film "Getting to Know You," directed by her sister, Lisanne Skyler, and adapted from short stories by Joyce Carol Oates. The film starred Zach Braff, Chris Noth, Heather Matarazzo and Bebe Neuwirth and premiered in the Dramatic Competition at the Sundance Film Festival, the 'Critics Week' section of the Venice Film Festivals, and received "Two Thumbs Up" from Ebert and Roeper.

In 2005, the Actress Julia Stiles hired her to adapt Sylvia Plath's iconic novel The Bell Jar for the screen. Her screenplay won the support of the top Plath scholars in the world, and she was asked to participate in Plath's induction into the American Poet's Corner at St. John's Cathedral in New York City. That same year, she found Robert Kanigel's acclaimed biography The Man Who Knew Infinity and originated and executive produced the film adaptation with the writer/director. The Man Who Knew Infinity tells the story of the self-taught Indian math genius Srinivasa Ramanujan, whose work is considered the foundation of the digital age. The film, starring Dev Patel and Jeremy Irons, made its world premiere at the 2015 Toronto International Film Festival and was distributed in the US and globally in 2016. It was screened at the White House by the Office of Science and Technology in October 2016, and featured in the Breakthrough Prize ceremony in November 2016.

In 2015 it was announced that Skyler had co-written with Scarlett Johansson, who will also direct, an adaptation of Truman Capote's lost novella Summer Crossing which was rediscovered and published in 2005.