Cruise, 49, and Holmes, 33, have a daughter, Suri, age six. Holmes has been absent from premieres for Cruise's latest film, Rock of Ages.
Cruise's lawyer Bert Fields said Holmes filed for divorce on Thursday.
"Kate has filed for divorce and Tom is deeply saddened and is concentrating on his three children," Amanda Lundberg told The Associated Press. "Please allow them their privacy to work this out."
Holmes' attorney Jonathan Wolfe has issued a statement, saying: “This is a personal and private matter for Katie and her family. Katie's primary concern remains, as it always has been, her daughter's best interest."
Cruise was previously married to actresses Nicole Kidman and Mimi Rogers. He has two older children with Kidman. He and Holmes were wed in an Italian castle in 2006.
It was a first marriage for Holmes, who admitted she'd had a crush for years on the Top Gun star, who is a follower of Scientology. Their relationship and the birth of their first child took place under intense scrutiny from the tabloids.
Cruise is currently in Iceland working on the movie, Oblivion. Holmes is working on an as-yet-untitled film directed by Christian Camargo that is a modern retelling of Anton Chekhov's The Seagull.