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- Lewis Black as The Narrator
- Ron Rifkin as Henry Meyerwitz
- Lesley Ann Warren as Marilyn Meyerwitz
- Ben Schwartz as Nathan Meyerwitz
- Michael C. Hall as Jack Meyerwitz
- Sarah Silverman as Cheri Meyerwitz
- Rainn Wilson as Joel Meyerwitz
- Kate Mara as Meg
- Judy Greer as Laura
- Stephen Tobolowsky as Ephraim
- Taraji P. Henson as Mary
- Alicia Witt as Amy Harrison
- David Packer as Eli
- Octavia Spencer as Alison
- Geoffrey Arend as Dr. Novak
- Guillermo Diaz as Jesus
- Troian Avery Bellisario as Film Set P.A.
- Deborah Pratt as Cassandra Williamson
- Leslie Speight as Wizdom
- Raja Fenske as Rajeev