- John Steven Rocha - Bellaramine (voice)
- Paul Telfer - Angry Scholar #2 (voice)
- Jonathan Morgan Heit - John Herschel (voice)
- Cary Elwes - Edmond Halley / Robert Hooke (voice)
- Tom Konkle - Samuel Pepys (voice)
- Alexander Siddig - Isaac Newton (voice)
- Alfred Molina - Ibn al-Haytham (voice)
- Richard Gere - Clair Patterson (voice)
- Marc Worden - Harrison Brown (voice)
- Kirsten Dunst - Cecilia Payne (voice)
- Marlee Matlin - Annie Jump Cannon (voice)
- Peggy Jo Jacobs - Margaret Harwood (voice)
- Amanda Seyfried - Marie Tharp (voice)
- Stoney Emshwiller - Guard (voice)
- Christiane Amanpour - Enheduanna (voice)
- André Sogliuzzo - Christopher Wren (voice)
- André Sogliuzzo - Weichelberger (voice)
- Oliver Vaquer - Joseph von Fraunhofer (voice)
- Christopher Emerson - Acolyte (voice)
- Fred Tatasciore - Democritus (voice)
- Piotr Michael - Lab Assistant (voice)
- Piotr Michael - Edmund Muskie (voice)
- Enn Reitel - Henry Norris Russell (voice)
- Keythe Farley - (voice)
- Martin Jarvis - Humphry Davy (voice)
- Fay Masterson - (voice)
- Heiko Obermöller - Einstein's Father (voice)
- Julian Ovenden - Michael Faraday (voice)
- William Salyers - (voice)
- Paul Sorvino - Augustin Mouchot (voice)
- Eliza Schneider - (voice)
- Frank Baxter - Self (archive footage)
- John F. Kennedy - Self (voice) (archive footage)
- Harssh A. Singh - Ashoka (voice)
- Seth MacFarlane - (voice)
- Seth MacFarlane - Giordano Bruno (voice)
- Seth MacFarlane - Sherwood Rowland (voice)
- Seth MacFarlane - President Harry S. Truman (voice)
- Patrick Stewart - William Herschel (voice)
- Carol Bach Rita - Caroline Herschel (voice)
- Viggo Mortensen - Nikolai Vavilov (voice)
- Ken Lally - (voice)
- Phil Crowley - (voice)
- Yuri Lowenthal - (voice)
- Edita Brychta - (voice)
- Christopher Lee Parson - (voice)
- Andrew Pifko - (voice)
- Brendan Bradley - (voice)
- Carl Sagan - Self (archive footage)
- Carl Sagan - Self (voice) (archive footage)
- Matthew Jayson Cwern - (voice)
- Alan Shearman - (voice)
- Natasha Goubskaya - (voice)
- Marcelo Tubert - (voice)
- Rick Pasqualone - (voice)
- Elijah Braik - (voice)
- Novi Brown - (voice)
- Steve Oatway - Charles Darwin
- Adam Tsekhman - Christiaan Huygens
- Neil Arnote - Neil Armstrong
- Judd Hirsch - Robert Oppenheimer (voice)
- Olivia d'Abo - Marie Curie (voice)
- Trang Vo - Birthmark Woman
- Trang Vo - (voice)
- Alex Bartram - Samuel Sagan
- Brannon Braga - World's Fair Attendee
- Marcello Guedes - Young Neil deGrasse Tyson
- Leandro Guedes - Young Stephen Joseph Tyson
- Coby Greenberg
- Alan Silvestri
Cary Elwes hace el papel de Edmond Halley / Robert Hooke (voice).
Patrick Stewart interpreta a William Herschel (voice) en la serie.
Viggo Mortensen interpreta a Nikolai Vavilov (voice) en la serie.
Alexander Siddig interpreta a Isaac Newton (voice) en la serie.
Alfred Molina hace el papel de Ibn al-Haytham (voice).
Richard Gere hace el papel de Clair Patterson (voice).
Kirsten Dunst hace el papel de Cecilia Payne (voice).
Neil deGrasse Tyson interpreta a Self - Host en la serie.
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