The 38-year-old actress earned the title also bestowed on the likes of Julia Roberts and Sandra Bullock thanks to a string of roles in romantic comedies such as Legally Blonde and Sweet Home Alabama.
However, it's not a title she ever wanted!
Reese told the new issue of Glamour magazine: "I certainly didn't self-identify as anyone's sweetheart. I'm friendly, but I don't think I'm sweet. I'm honest."
The mother-of-three has grown up in front of the camera and admitted it took her a long time to realise what makes her happy.
"I don't think I realised [in my twenties] that no one else makes you whole. You have to take responsibility for your own happiness," she said.
"That took me until I was about 31 to know. It wasn't easy to realise, Oh, wait, I am purely responsible [for my life] - no relationship, no children, no nothing is going to make you a happy person. Every day you have to choose to find and cultivate your own happiness."
And now she is very happy thanks to her three kids Ava, 15, Deacon, 11, and Tennessee, two, and husband Jim Toth.
"It's really wonderful being with somebody who supports me, who loves me, who is my number-one fan," she said of Hollywood talent agent Jim.
"That is such an incredible experience. You have to be ready for those things. I had to be in a place where I felt all those things about myself."
Reese, 38, married Hollywood agent Jim in March 2011, the father of Tennessee. Previously, she was wed to fellow actor and Cruel Intentions co-star Ryan Phillippe, who is the dad of Ava and Deacon.
Reese can next be seen in movie Wild, based on the book by Cheryl Strayed.
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