Clayton is best known for starring as Nomi Marks in the Netflix original series Sense8, Sasha Booker in the third season of Designated Survivor and Tess Van De Berg in Showtime's The L Word: Generation Q.

[3][4] Her father, Howard Clayton, was a criminal defense attorney, and her mother, Shelley, is an event planner.

[11] Clayton starred as one of the eight main characters in the Netflix original television series Sense8 that premiered on June 5, 2015.

[12] In Sense8, she played Nomi Marks, a trans woman, political blogger, and hacker living in San Francisco.

[13] Clayton said that she was primarily interested in Sense8 because of the opportunity to play a transgender character written by filmmakers Lilly and Lana Wachowski and to be on set with them.