Santiago-Hudson was born in Lackawanna, New York, the son of Alean Hudson and Ruben Santiago, a railroadworker. His father was Puerto Rican and his mother was African American. He graduated from Binghamton University. He wrote Lackawanna Blues, an autobiographical play in which he portrayed himself and some twenty different characters from his past, which he adapted for a highly-acclaimed, award-winning 2005 HBO film that won him the Humanitas Prize and earned him Emmy and Writers Guild of America Award nominations.

Santiago-Hudson appeared on Broadway in Jelly's Last Jam and received the 1996 Tony for August Wilson's Seven Guitars. Santiago-Hudson's screen credits include Coming to America and Domestic Disturbance. On television he has appeared on the daytime dramas Another World and All My Children and the primetime series The Cosby Mysteries, New York Undercover, NYPD Blue, Touched by an Angel, The West Wing, Third Watch, Law & Order: Special Victims Unit, and five episodes of Law & Order (which coincidentally stars Lackawanna Blues star S. Epatha Merkerson), among others.

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