Andy Brewster (Seth Rogen) is an organic chemist who has just invented Scioclean a cleaner that is safe for the environment and better than what is out there. He wakes up early in the morning to many phone calls from his mother, Joyce (Barbra Streisand), before going to K-Mart for a pitch to sell his product. He is very nervous and bombs the pitch. He lives in California and is flying into New Jersey before embarking on a road trip east to west to many companies to sell his product. Joyce picks him up at the airport and is a typical mother nonstop talking, trying to feed him, etc.
Andy is very tired, but Joyce talks him into having dinner with her and her friends. They talk about a singles group they want Joyce to go to and other random things. After they leave Andy tells her he’s tired and wants to go to bed, but she’s disappointed because she got out all the old home movies for them to watch. He goes to bed but later goes to apologize to her where he finds her asleep in bed with the home movies playing and M&Ms in her hand.
The next night he goes to the singles group with Joyce. She turns all the men away. Instead of explaining why she won’t date (her husband died when Andy was 8), she turns it around on him and suggests he go to therapy since he can’t find a wife.
They start talking, and she tells him that her friend suggested she tell him about the boy she fell in love with in Florida. When she was 19 she went to Florida and fell in love with a boy named Andy Margolis who also lived in Manhattan. When they went back home they started dating, but he didn’t want to be serious. She started dating her husband at the same time, and when he proposed, she told the guy named Andy hoping that he would beg her to marry him instead, but instead told her to get married and she was devastated. She named her son Andy because you want to name your son after someone that you love.
Andy goes to his computer and looks up her old boyfriend and finds out that he lives in San Francisco. He decides to add that stop to his road trip. The next morning, his mother starts harassing him about past relationships. Andy asks Joyce to go on his road trip with him, and she obviously is overjoyed. They go to the Budget rent-a-car, and she won’t shut up about him asking for a discount and although he wants an SUV she convinces him to get a small car and uses a coupon. She makes him listen to a book on tape called Middlesex about a hermaphrodite. They talk about Andy Margolis, and she tells him that he was the first person to tell her that she was beautiful.
At the first meeting in VA, Joyce wants to go into the meeting with Andy, but of course he won’t let her. The meeting does not go well, but he tells her that it does so she won’t bother him. At another meeting that day, he also has a bad pitch. While in the car, they pass a hitchhiker. She tells him never to pick up a hitchhiker because they are all rapists. They get to a cheap hotel, and she insists on only one room. He practices the pitch and she criticizes him, telling him that he should drink it to prove that it’s healthy.
In Tennessee the next day, it’s snowing very badly. He thinks they have a flat tire, so they pull over at what happens to be a strip club. They go inside, and one of the strippers helps them fix their car before they’re on their way again, but they have nowhere to stay. Joyce calls Andy’s ex-girlfriend Jessica and she and her husband pick them up and let them stay with them for the night. We find out that Andy proposed to Jessica when they were 18, but she told him no, and he broke up with her. Joyce did not know this. Andy is upset with Joyce the next day in the car because she won’t butt out of his life.
The next meeting is in Texas at Costco. This time they come around to the tables for the pitch. Joyce is there and starts talking with the guy about how he should change the label and name to which Andy flips out on the Costco guy that he is not changing the name. Obviously that meeting does not end well. That night in the hotel Andy is depressed, drinking. She starts nagging him about staying hydrated while he drinks. He snaps at her, and she snaps back calling him a little shit and how she can’t do anything right. She knows why he went to UCLA it was to get away from her. She leaves, and he finds her later on in the hotel bar. The guy in the bar keeps hitting on her and wants to give her another drink, but Andy prevents this and they get into a fight, so he now has a black eye.
They talk in the car the next day, and he tells her that he went to UCLA because it has the best organic chemistry program in the country, not because he wanted to get away from her. They stop at a steakhouse. He tells her that he spent all his money on the product and now he doesn’t know what he’s going to do. To save money, she decides to take on the challenge where she’ll eat a 4 ? lb steak, and the rest of a giant meal in 1 hour if she does it, she’ll get it for free. If not, it’s $100. She goes to the front of the restaurant and takes on the challenge. A man named Ben (Brett Cullen) is fascinated by how well she is doing and starts giving her tips (he’s seen this contest a lot). She wins! On the way out he talks to her and gives her his number he does business in NYC and wants to take her out.
Andy and Joyce are finally getting along. They are on CD 10 out of 22 of Middlesex. He naps in the car, and she picks up a hitchhiker. They stop at the Grand Canyon before finally getting to Vegas. They go to Caesar’s Palace, and she plays the slots at a frog machine (she loves frogs) and wins $60, so she gets her ears pierced. She shows up in the morning after being out all night. She tells him that she wants to stay in Vegas for a few days while he goes on to San Fran. He tells her the truth about San Fran, and while she’s not mad, she is upset.
He goes to his pitch for the Home Shopping Network, which is actually set up like the show. He starts the pitch but everyone is bored, and he’s running out of time. Joyce walks in, and when he sees her, he decides to take all the advice she gave him about the pitch and loosens up. He actually drinks the cleaning liquid, and they all love it and want the product.
They decide to go to San Francisco together. She calls Andy Margolis in the car, but she is so nervous she just hangs up. They decide to just show up at his house. His son (Adam Scott), also named Andy Margolis, answers the door. His father died 5 years ago. He invites them inside, and they talk. He never knew anything about Joyce. Just then his sister shows up. She introduces herself her name is Joyce. Andy named his daughter after her.
In the car, Joyce is now very happy. She thought she never mattered to him, but she did. And she doesn’t regret marrying her husband because he gave her Andy. He’s the love of her life. They finish the book. This has been the best week of her life. They say goodbye, and they love one another. On her way to her gate, he sees her pick up her phone. He thinks she’s calling him already, but no she’s calling the cowboy Ben. She’s finally going to move on.
During the credits, we see a lot of scenes of them in the car, talking, having hilarious conversations.
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