Now she's coming back to theaters playing Drew Barrymore's sister in the new comedy "Going the Distance."
Applegate, whose known Barrymore since she was 8 years old, could relate to the role since she's an older sister in real life.
"I have a sister about the same age as Drew. I do feel that way with her. I feel like I really would strangle anyone who would hurt her," she joked.
Applegate went on to tell "Early Show" co-anchor Chris Wragge about her role in the film, actor Justin Long's nude scene, and her excitement to become a mother after surviving breast cancer.
"Going the Distance" opens nationwide on Friday, Sept. 3.
Watch Appelgate's interview on "The Early Show":