- Harris Yulin - Father Lavie
- Bruce Greenwood - Dr. Hume
- Marcello Fonte - Domenico Onofrio Tempesta
- Sue Jean Kim - Dr. Yup
- Michael Simon Hall - Stuart Feinstein
- Gina Costigan - Mrs. O'Meara
- Steven Cox - Boyfriend of Dr. Hume's Daughter
- MorningStar Angeline - Nabby Drinkwater's Wife
- Al Linea - Abruzzi
- Richard Fitch - Mill Foreman
- Amy Lynn Stewart - Merciful Mother
- Guillermo Díaz - Sergeant Mercado
- Marylouise Burke - Librarian
- Brian Goodman - Al
- Sandra Berrios - Social Worker at Hatch
- Laura Silverman - Kristin
- Christine Parks - Humanities Department Chair
- Morgan Sullivan - Office Buddy
- Jake Robards - Landlubbers (voice)
- Michael Genet - Thomas' Surgeon
- María Gonzalez - Ma's Oncology Nurse
- A.C. Peterson - Gene Diogenes
- Christopher J. Hanke - Thad
- James Quattrochi - Bus Driver
- Rachel B. Joyce - Jeanette
- Paul Coleman - Support Group Counselor
- Brandon J. Dirden - Kyle's Dad
- Katt Masterson - Doreen
- Jason Furlani - Larry Penn
- Annie Fitzgerald - Miss Hanker
- Joseph Ragno - Henrey Rood
- Joseph Ragno - Henrey Hood
- Jaiden Klein - Marie Sexton
- Oliver Patnode - Otero
- Felix Solis - Nurse
- Laura Esterman - Ruth Hood
- Joe Grifasi - Steve Falice
- Derek Goh - 17-19 Year Old Dominick & Thomas Acting Double
- Raymond Neil Hernandez - Omar
- Simone Coppo - Vincenzo Tempesta
- Sean Cullen - Dr. Yates
- Federico Dordei - Nunzio Tucci
- Agatha Nowicki - Angie Constantine
- Irene Muscara - Prosperina Tucci
- Shannon Plumb - Charlotte
- Tatanka Means - Nabby Drinkwater
- Donnie Masihi - Young Dominick Birdsey
- Wayne J. Miller - Mourner Wayne
- Thomas Gionet-Lavigne - Ray's Orderly
- Robert Mladinich - Paddy Wagon Officer
- Philip Ettinger - Early Adulthood Dominick Birdsey / Thomas Birdsey
- Aisling Franciosi - Young Dessa Constantine
- Destry Allyn Spielberg - Dr. Hume's Daughter
- Imogen Poots - Joy Hanks
- Roberta Riganò - Ignazia Tempesta
- Juliette Lewis - Nedra Frank
- Wally Lamb
- Anya Epstein
- Lynette Howell Taylor
- Jamie Patricof
- Derek Cianfrance
- Glen Basner
- Mark Ruffalo
- Tony Volante
- Harold Budd
- Daniel Timmons
- Jim Black
- Mariusz Glabinski
Joe Grifasi interpreta a Steve Falice en la serie.
Mark Ruffalo hace el papel de Dominick Birdsey / Thomas Birdsey.
Juliette Lewis interpreta a Nedra Frank en la serie.
Harris Yulin interpreta a Father Lavie en la serie.
Melissa Leo interpreta a Concettina Ipolita Tempesta 'Ma' Birdsey en la serie.
Rosie O'Donnell interpreta a Lisa Sheffer en la serie.
Archie Panjabi hace el papel de Dr. Patel.
Kathryn Hahn hace el papel de Dessa Constantine.
John Procaccino interpreta a Ray Birdsey en la serie.
Rob Huebel interpreta a Leo en la serie.
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