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Barrymore and Ben Stiller play newlyweds who buy a duplex only to discover it comes with the most annoying of tenants.
It becomes a battle royale with the elderly woman who has out-stayed numerous earlier owners, as well as her welcome.
"When I moved into my very first apartment, there was an older woman who lived upstairs," says Barrymore. "I don't know what I did to make her angry, but it must have been something pretty big in her mind."
"She would pound on the floor no matter what I was doing and she'd vacuum her hardwood floors at 3 a.m.
"That was such a crazy time in my life and she made it even crazier."
The L.A. courts had just granted Barrymore, who was 14 at the time, permission to be her own guardian.
"I never said anything to her, but I was so secretly upset with her for not telling me what the deal was. I wanted to prove so much I could succeed at being on my own."
Barrymore lost the battle.
"She was there long before I got there and she's probably still there. I think it was a real territorial thing for her."
Barrymore, 28, has had numerous apartments and houses since this incident, but there's still the question of her lineage that needs putting in perspective.
Her life has come with a great deal of baggage.
"I'm very proud of my family tree. The acting part of it started back in the 1700s.
"There were these two families of actors, the Drews and the Barrymores and they married into each other.
"I want to really understand that legacy because when I have children, their father will have to share that history with me.
"My grandparents had departed before I ever became an actor, but I know they influenced me cosmically.
"In a very unburdened way, I am anxious to keep the name and the tradition alive. I hope they're proud of my work."
Barrymore is trying to produce as many of her projects as possible to have "more input and control.
"As simply an actor for hire, you don't have the luxury of choosing the writers, directors and actors you work with, but it is a luxury that comes with a double-edged sword.
"You also have to take the brunt of the criticism when you start wearing multiple hats."
Barrymore is determined to add a director's hat to her credits.
"Directing is something I very much want to do. I'm working towards something but it's still in the distant future."