Holmes filed divorce papers this week in New York while her husband was in Iceland filming a movie.
Her move may have taken Cruise very much by surprise, according to some observers.
This was Cruise's third marriage. Oddly, all three marriages ended when each of his wives turned 33 years old.
In a world of larger-than-life celebrity marriages, none was subject to more tabloid fascination than that of Cruise and Holmes.
Married in 2006, the couple raised one child, Suri, now 6. Holmes reportedly is asking for sole custody.
The romance began as Cruise's career was hitting a rocky patch with his now-infamous couch-jumping episode, while Holmes was mostly known as the teen star of the TV drama "Dawson's Creek."
Gossip websites are reporting Holmes is asking for the divorce, in part, to get out of her more-famous husband's shadow and further her acting career.
Cruise has been down this road twice before: He was divorced from Oscar-winner Nicole Kidman after 10 years of marriage, and a three-year union with actress Mimi Rogers ended in 1990.
For some observers, it was only a matter of time before this marriage came to an end, as well.
But Entertainment Tonight's Christina McLarty disagrees.
She spent time with Cruise on the set of his latest film two weeks ago, and they talked about his marriage.
"There was nothing but love that I felt from his end," she says. "So, it is a little concerning and it is shocking, because ... there's an argument there that, you know -- was he blindsided by this divorce?"
Some saw signs of trouble when Holmes was absent during the publicity tour for Cruise's recent movie "Rock of Ages," but the actor, who turns 50 Tuesday, gave nothing away.
McLarty says, "When I asked him, at the age of 50, 'What's your greatest achievement?' he said, 'My marriage and my family."'
Julie Dam, assistant managing editor of People magazine, which broke the story, calls word of the pending divorce "a bombshell."
"It's one of the biggest marriages in Hollywood breaking up in the middle of summer," she said on "CBS This Morning: Saturday," when, just a couple weeks ago, Tom Cruise was talking about how wonderful his marriage was and his life was.
"Katie was the one who filed for divorce, in New York and, from how it went down, it certainly seems that Tom was blindsided."
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