- Keith Carradine - Captain Richard H. Pratt
- Craig Sheffer - Older Robert Wheeler
- Keri Russell - Naomi Wheeler
- Beau Bridges - Stephen Hoxie
- Christian Kane - Abe Wheeler
- Matthew Settle - Jacob Wheeler
- Gary Busey - Johnny Fox
- Sean Astin - Martin Jarrett
- Alan Tudyk - Nathan Wheeler
- Eric Schweig - Sitting Bull
- Tyler Christopher - Jacob Wheeler Jr.
- John Terry - Older Jacob Wheeler
- Daniel Gillies - Ethan Biggs
- Kwesi Ameyaw - Henry Foster
- Michael Spears - Dog Star
- Annabella Piugattuk - Dancing Water
- Russell Means - Older Running Fox
- Emily Holmes - Leah Wheeler
- Jay Tavare - Chief Prairie Fire
- Nathaniel Arcand - Brings Horse
- Gil Birmingham - Older Dog Star
- David Richmond-Peck - Sergeant
- Zahn McClarnon - Running Fox
- Balthazar Getty - David Wheeler
- Jonathan Scarfe - General George A. Custer
- Tom Berenger - Colonel J. Chivington
- Sheila Tousey - Older Thunder Heart Woman
- Tonantzin Carmelo - Thunder Heart Woman
- Christian Bocher - Bloody Bill Anderson
- Richard Speight Jr. - Rupert Lang
- Glen Powell - Jackson Wheeler
- Jeremiah Bitsui - Sgt. Red Tomahawk
- Wes Studi - Black Kettle
- Francesco Quinn - Captain De Salamanca
- Chris Browning - Trooper Long
- Avu - Lakota Woman
- James Kirk - Jeremiah Wheeler
- Graham Greene - Conquering Bear
- Tyler Posey - Young Abe Wheeler - 12
- Christopher Heyerdahl - James “Jim” Ebbets
- Jesse Moss - Rider #1
- Brandon Oakes - Kicking Bear
- Chris Enright - Leland
- Larry Rapaport
- Wendy Hill-Tout
- Michelle Wong
- Steven Spielberg
- Geoff Zanelli
Will Patton interpreta a James Fletcher en la serie.
Jessica Capshaw interpreta a Rachel Wheeler en la serie.
Josh Brolin hace el papel de Jedediah Smith.
Matthew Modine hace el papel de Samson Wheeler.
Lance Henriksen interpreta a Daniel Wheeler en la serie.
Irene Bedard hace el papel de Margaret Light Shines Wheeler.
Garrett Wang interpreta a Chow-Ping Yen en la serie.
Skeet Ulrich hace el papel de Jethro Wheeler.
Rachael Leigh Cook interpreta a Clara Wheeler en la serie.
Keith Carradine interpreta a Captain Richard H. Pratt en la serie.
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