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Reiner formed a comedy duo with Brooks in "The 2000 Year Old Man" and acted in such films as It's a Mad, Mad, Mad, Mad World (1963), The Russians Are Coming, the Russians Are Coming (1966), and the Ocean's film series (2001–2007). He co-wrote and directed some of Steve Martin's first and most successful films, including The Jerk (1979), and also directed such comedies as Where's Poppa? (1970), Oh, God! (1977), and All of Me (1984). Reiner appeared in dozens of television specials from 1967 to 2000, and was a guest star on television series from the 1950s until his death. He also voiced characters in animated films and television series, including the TV series Father of the Pride (2004–2005), in which he voiced Sarmoti, and was a reader for books on tape. He wrote more than two dozen books, mostly in his later years.

He was the recipient of many awards and honors, including 11 Emmy Awards, one Grammy Award, and the Mark Twain Prize for American Humor. He was inducted into the Television Hall of Fame in 1999.