The pair are in line to reunite with their The Way Way Back directors Jim Rash and Nat Faxon, reports The Wrap.
Kristen Wiig will star in the Indian Paintbrush production about a cash-strapped woman who agrees to smuggle black market organs.
Rockwell will play her partner in crime, with Janney as her intimidating, polyamorous boss.
Rash and Faxon wrote the script and will also re-team with The Way Way Back producer Kevin J Walsh.
Janney can currently be seen in CBS sitcom Mom with Anna Faris. She will next appear with Melissa McCarthy in Tammy and romantic comedy The Rewrite.
Rockwell will feature with Keira Knightley in Laggies. He recently wrapped the Poltergeist remake.
The Heart will begin shooting in North Carolina in May.