- Ames McNamara - Mark Conner-Healy
- Jayden Rey - Mary Conner
- Emma Kenney - Harris Conner-Healy
- Alicia Goranson - Becky Conner-Healy
- Alicia Goranson - Becky Conner
- Sarah Chalke - Becky Conner-Healy
- Shelley Winters - Nana Mary
- Joe Grifasi - IRS Office Supervisor
- Jay O. Sanders - Ziggy
- Glenn Quinn - Mark Healy
- Ned Beatty - Ed Conner
- Joseph Gordon-Levitt - George
- Ellen DeGeneres - Dr. Whitman
- Vicki Lawrence - Phyllis Zimmer
- Michael O'Keefe - Fred
- Arianna Huffington - Estree Longet
- Sandra Bernhard - Nancy
- Leonardo DiCaprio - Darlene's Classmate
- Martin Mull - Leon Carp
- Mariel Hemingway - Sharon
- Johnny Galecki - David Healy
- Natalie West - Crystal Anderson-Conner
- Danielle Harris - Molly Tilden
- Danny Masterson - Jimmy
- Florence Henderson - Flo
- James Pickens Jr. - Chuck Mitchell
- Phil Leeds - Grandmama Lily
- Tom McTigue - Doctor
- Erick Avari - Prince's Assistant
- Mo Gaffney - Astrid Wentworth
- Jim Varney - Prince Carlos
- Dana Gould - Chip
- Ronald E. House - Werner
- Dina Merrill - Doris
- Grinnell Morris - Skip
- Iqbal Theba - Dr. Bakshi
- Hillary Tuck - Kiki
- Callan Farris - Kazim
- Molly David - Woman in Coffee Shop
- Brent Pope - Valente
- David Mendenhall - Clerk (uncredited)
- Rhea Seehorn - Carrie
- Stevie Sterling - Stripper (uncredited)
- Jonathan Mangum - Flip
- Zoe Perry - Little Jackie
- Zoe Perry - Young Jackie
- Andi Chapman - Denise the IRS Information Clerk
- Mark Lowenthal - Ed the IRS Office Clerk
- Monty Hoffman - Man in Line
- Jodi Long - Woman in Line
- Gail Mancuso
- Andrew D. Weyman
- Gary Halvorson
- Philip Charles MacKenzie
- John Pasquin
- Mark K. Samuels
- Carrie Fisher
- Martin Pasko
- Joel Madison
- Norm Macdonald
- Steve Paymer
- Debbie Kasper
- Tom Werner
- James Berg
- Chuck Lorre
Ellen DeGeneres interpreta a Dr. Whitman en la serie.
Joe Grifasi interpreta a IRS Office Supervisor en la serie.
Sandra Bernhard hace el papel de Nancy.
Phil Leeds interpreta a Grandmama Lily en la serie.
Roseanne Barr interpreta a Roseanne Conner en la serie.
John Goodman interpreta a Dan Conner en la serie.
Sara Gilbert interpreta a Darlene Conner en la serie.
Alicia Goranson hace el papel de Becky Conner-Healy.
Michael Fishman interpreta a D.J. Conner en la serie.
Laurie Metcalf interpreta a Jackie Harris en la serie.
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