Catherine Hardwicke has had one of the decade’s more mercurial directing careers. After winning acclaim for 2003’s gritty “Thirteen,” her résumé began to look like a case study in the unpredictability of Hollywood’s studio films. 2005’s slick “Lords of Dogtown” coasted on Heath Ledger’s performance, while the following year’s tame “Nativity Story” fell short of the Christmas cash cow one might hope for. Hardwicke rebounded with the lucrative first installment in the “Twilight” franchise, but 2011’s “Red Riding Hood” attempted to capture the same demographics with less success. Her 2013 erotic thriller, “Plush,” made all of $3,080 at the box office.

Now she’s departed from the teen-oriented features that comprise her career, and the results make for arguably her best movie since “Thirteen.” “Miss You Already,” which opens on Friday after premiering at September’s Toronto Film Festival, stars Drew Barrymore and Toni Collette as lifelong best friends who must cope with the latter’s sudden breast-cancer diagnosis. Think “Beaches” set in London, with Collette playing the narcisisstic party gal and Barrymore her down-to-earth support system. Hardwicke, helming a script by Morwenna Banks, extracts a rich comedic rapport from the two women, who have natural chemistry that will make you wonder why no one has thought to cast them together before.

As strong filmmakers are wont to do, Hardwicke positions “Miss You Already” as an extension of her previous work. The Huffington Post sat down with the 60-year-old director to discuss her weepy girl-power ode, that time a studio told her she couldn’t direct a movie because she’s not a man and why her new motto is “vote with your ass.”

This movie is going to excite a lot of longtime “Beaches” fans. I was excited about it.

I’m excited because my favorite thing is HuffPost.When we did the test screening, we’d ask them to put their favorite website that you go to every day, and everybody put you guys. I was like, “Oh, you guys have the ear of the public.”

How were those test screenings?

We only had one test screening. That’s all we could afford because it’s an indie movie, and it went really awesome. It was in a red state-type thing, so it was Middle America, which was kind of fun. They frickin’ loved it. I was there in the focus group and these “normal” people really connected to the movie. They laughed their heads off and had some waterworks when it was appropriate. The men dug it!

I do think it’s a surprisingly male-friendly movie, if we want to feed into that binary.

Yeah, and look at the three guys. They’re hot.

Yeah, can we just objectify the men in this movie for a minute?

Okay, for one minute! You’ve got Dominic Cooper as Toni’s husband, love it. Tyson Ritter, yum yum. And then Paddy Considine as Drew’s husband is so soulful. They’re all really good. But that was one of the things I wanted to do. I really wanted to make them all dimensional, like real people. I wanted to give them dogs and jobs and weird shit and to defy your expectations. I think, with Dominic Cooper, most people would think he’s going to cheat and he doesn’t. He’s a standup guy. He’s a good dad! And look at the role models we usually have for men in movies. Either they go out and avenge the kidnapping of their daughter and they’ll kill a million people, or they’re just a man-child, not grown up — goofy, dumb, infantile. But these guys are really cool guys.

It’s Toni’s character who’s complicated. Some might call her unlikable, that other silly binary.

She’s a mess. She admits that she’s a narcissist and has a huge ego and that she’s selfish. And she is. But if somebody is unlikable in a weird way, you almost like them more than if they are a perfect saint. We can’t all relate to the perfect. However, it’s weird because Drew’s character is pretty damn great and I still love her.

It’s the balance.

And you want Drew to be your best friend, right? You already love her and you already feel her heart.

But you had the two roles reversed at one point, right?

Actually, they reached out to Toni before I was on the project. Toni was originally Drew’s character, but that’s the role she always plays. She did it in “In Her Shoes.” She was the more dowdy one. Or, not dowdy, but the more solid one. Cameron Diaz is the hot mess. I thought it was so much more fun if you see Toni start out all glamorous and fabulous. And then, of course, Toni is brave enough to go on camera and get her head shaved. She went all the way to unglamorous.

That head-shaving is probably the most special scene in the movie. I assume you only had one take to get it?

Oh yeah. That’s real. Frances de la Tour, from “Harry Potter,” is literally shaving her head. It was scary.

Was that the most nerve-racking day?

Dude. It was totally nerve-racking. When we asked if anybody could volunteer to get their head shaved so Frances can practice, one guy said okay and let her shave his head. So she’d done one head. She’s a great British actress — she’s super funny, her voice and everything — so she sits Toni down like, “Are we okay?” We’ve got the cameras and I said “Frances, do you feel comfortable? You’re going to start here and go here, etc.” And she goes, “Great!” And then she just starts going, so fast. I’m like, “Slow down!” She was so confident, just whipping through, and I’m like, “Dude! I can’t even catch this on film.” She was so brave, and Toni was just sitting there fully brave. She was really in the moment because it’s really happening. Her hair is going away. She’s not going to have that pretty hair for a year. Think about how anybody would feel. It was damn real for her.

“Miss You Already” fits in with your past work in surprising ways, most clearly in its parallels with “Thirteen.” Both deal with two people enacting a certain dependency and then growing up within the confines of that.

Oh, I like that.

Thinking broadly, what attracts you to those types of stories? And more specifically, do you see “Miss You Already” as a natural segue within your films?

I do see it closest, in a way, to “Thirteen.” I think you’re spot-on on that because “Thirteen” was kind of like a triangle. The mother was important in that, and then the two friends trying to find their friendship and twisting it and bending it and breaking up, and then going back to the mother, who was the original friend in that case. And in this case, it was the two friends that are having this strain. They twist and turn and try to find the balance and try to love each other while going back to the original friend. It’s almost the reverse of the triangle of “Thirteen,” but they end up together with this solid person that was really their platonic love story. Drew said to me when I first met her that her favorite movies are platonic love stories. I thought, “Oh, that’s so cool.” This is such a love story when you see Drew and Toni. They love each other so much. It’s a beautiful love story.

In terms of financing, getting this movie made couldn’t have been easy, even with Jennifer Aniston attached at one point.

We know it’s difficult, because how many female-directed movies get financed? Only 4 percent. And then how many star women? That’s only 25 percent. So the odds just keep getting smaller. The fact that this one got made, and “Suffragette” and a few other movies like this, fought the odds. It was that one sperm that made it.

Did it require officially casting the two leads to get everything cemented?

Oh yeah. Actually, Toni was already involved, but we had to have the other component, so when Drew said yes, we literally had nine weeks to start shooting. Our producer had to pull the financing together, we had to get a whole crew, all the locations and all the rest of the cast in a foreign country in nine weeks. There are obviously great professional crews in London. That goes without saying. However, we didn’t necessarily get them because they were doing “Star Wars” and all the big-budget movies. It was like “Death Race 2000.” I mean, it was exciting.

Speaking of big movies, “Twilight” was heralded as the highest-grossing release by a female director at the time.

Yeah, $69 million opening weekend. I think “Fifty Shades” beat it.

But you haven’t done much in the blockbuster realm since.

Well, we didn’t know that was going to be a blockbuster. Nobody knew that at the time because that was put into turnaround by Paramount. They said, “This movie isn’t going to make money, so we’re not going to make it.” Then Fox wouldn’t make it. Most studios wouldn’t make it because they all thought, “Oh, a girls’ book isn’t going to make money.” The literally said to me, “’Sisterhood of the Traveling Pants’ made $39 million and that’s all this movie will ever make.” I was like, “OK, but it seems like people online like it.” The studio literally said to me, “Hey, that could be 400 girls in Salt Lake City who could be the only people emailing about this.” I thought, “Really? It seems like it’s a few more than that.” And then the buzz started building and Stephenie Meyer wrote two more books while we were prepping the movie, and that was amazing. She’s really good with her fans, so she built up her fan base. Then it turns into this awesome blockbuster, but no one thought it was going to be, or else every other studio would have tried to make it, instead of this little upstart Summit.

Did you think you would get blockbuster offers after making that movie?

Yeah, I did.

And did they not come, or were you just not interested?

No, they didn’t come. I could have directed the next one because that was in my contract, but I didn’t feel for the other books like I felt for the first book. I liked the dizzy, falling-in-love stuff in the first book, and I didn’t really feel it in the second one, so I didn’t want to do the second one. But then “Red Riding Hood” made $90 million. That’s not too bad. We made it for less than half of that. But I felt like a lot of people felt … I thought the world would just totally open up to me because I’d started this mega-franchise. I thought I’d be able to get an office on a studio and people would say, “What do you want to do?” But that did not happen.

Was there a movie that you really wanted to direct?

Yes. There were a few, and even after the movie had made $400 million, my agent and I had read a script for another movie that I really loved. I had a whole take on it and was so excited. I knew the producer, and he let me go in and talk to him and pitch my take. The call came back. “They want a man.”

That’s literally what you were told?

“They want a man to direct this movie.”

What movie was it?

It was a movie where I love the director and I love what he did with it, so I don’t want to say anything negative because he didn’t know that I had ever wanted to do it. It was “The Fighter.” I loved the character drama of it. I had taken boxing classes. I was all into it. I loved the feeling of it. It was gritty like “Thirteen.” I said, “Have you seen ‘Thirteen’? I’m perfect for this.” They said, “Nope, we think a guy should do it.” I couldn’t even get the interview to go on from there. They wouldn’t even meet with me. Immediately you go, “OK, a guy can direct all the other ‘Twilights’ and ‘Sisterhood of the Traveling Pants’ and ‘Sex and the City.’ They can direct the girliest movies ever with no problem, but a woman can’t direct this? Unconscious gender bias, that’s what we’re all talking about. How do we get underneath that unconscious gender bias that women have and men have, break through that and stop so that more people don’t have to just hire their mini-me that looks exactly like them?

It’s such a cyclical myth that people don’t care about movies about women or other minorities.

Studios should go for diversity and actually say, “Let’s hire different kinds of people that look different than us and think different than us.” Every company that’s done that, like Google, has transformed their culture to be less biased and pale male. They’re more successful, more inclusive, their profits go up. Just think about “Orange Is the New Black.” That celebrates diversity and it’s popular! People love it. So let’s all get a clue, guys. We want to know about different characters.

I think that’s what’s so good right now. It’s like Meryl Streep talking about Rotten Tomatoes. Of course the movies are biased toward males. If there are 760 male critics and 180 women, when everybody in America says, “What movie should I see this week?” they’ll say, “Oh, I’ll go to the one that’s male stereotyped.” Then the males in power can say, “Hey, well, those are the movies that make money,” because those are the ones that are marketed with $100 million campaigns. Those are the ones that are sanctioned by the male critics. Our movie, which we want people to see, is written by a woman, directed by a woman, starring women in it, but how do we get the word out? How do we say to people to connect the dots that, if you want more diversity, support it by showing up? Then we can have ammo and say, “Hey, this movie, directed by a woman or about two women or about different kinds of people actually made money.” Those are the connections that we’ve got to make. Go there and vote with your butts in the seats. Vote with your ass! That’s our new motto!

“Miss You Already” opens Nov. 6. This interview has been edited and condensed.

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