Holmes, who married the actor after a whirlwind courtship, filed the divorce papers, according to Cruise's representative.
'Kate has filed for divorce and Tom is deeply saddened and is concentrating on his three children,' Cruise's representative said.
Holmes is understood to have cited 'irreconcilable differences' in the filing and is seeking 'primary residential custody' of daughter Suri, age six.
'This is a personal and private matter for Katie and her family,' Holmes's attorney said in a statement. 'Katie's primary concern remains, as it always has been, her daughter's best interest.'
Mission Impossible and Rock of Ages star Cruise, now 49, married Holmes, 33, in 2006 after dating for a number of months. Their relationship saw Cruise declare his affection for his wife in increasingly public, grandiose ways, including the infamous couch-jumping episode on Oprah.
The couple married in a castle in Bracciano, Italy in November 2006. The bride wore a custom-made Giorgio Armani gown.