Rob Lowe, who joined in season two, and Rashida Jones, who has been with the show from the start, will exit in the middle of the upcoming sixth season.
On screen, both have been an on-again, off-again couple.
Lowe is already starring in Killing Kennedy and currently appears in the HBO telemovie Behind the Candelabra.
Meanwhile Jones and her writing partner have a two-year deal with Warner Bros. Television to write and produce comedy and drama projects for both cable and network TV.
Source: The Hollywood Reporter