Peter Reynolds (Ed Helms) is a physician who spends his days performing rectal exams on his patients. He's also divorced and his son Ethan (Zachary Haven) has little respect for him.
Peter takes Ethan to attend the wedding of his mother Helen Baxter (Glenn Close). Peter's twin brother Kyle (Owen Wilson) is there with his pregnant girlfriend Kaylani (Jessica Gomes). Peter resents Kyle for living frivolously due to receiving royalties for including his image on bottles of hot sauce.
After the ceremony, Peter is watching "Law and Order" when he notices one of the actors looks familiar to him. After being told that their father died of colon cancer (which is what drove Peter to pick the job he has now), he suspects that his father may actually still be alive because the actor on the show has a birthmark similar to what Helen told the guys their dad had. Helen eventually admits that she lied about their father because she felt that their real dad wasn't fit enough to raise them. After Peter angrily presses Helen for more information, she relents and says their dad could be Terry Bradshaw. Peter gets excited because he idolized Terry growing up. Knowing he lives in Miami, Peter and Kyle make a trip to go find him.
On the plane ride to Miami, Kyle tries to play matchmaker for Peter with a stewardess. Peter is hesitant despite not being in a relationship with anyone since his ex-wife. Kyle wants to make it a side goal on their trip for Peter to get laid.
The brothers go to a stadium where Terry is having a meet-and-greet. Peter takes out a picture of Helen and shows it to Terry, leading him to reminisce fondly (and sexually) about Helen, which causes him to believe he really is Peter and Kyle's father. Terry invites them to his house and later plays catch on the beach with Peter. When Kyle is thrown the ball, he runs to catch but gets knocked on his ass by Terry's friend Rod Hamilton (Ving Rhames). He also has pleasant, steamy memories of Helen. When Peter mentions a trip that Helen supposedly went on with Terry to Australia around the time of the guys' conception, Terry mentions that she never went with her, so he couldn't be their father. Terry and Rod mention a man that Helen later dated named Roland Hunt (J.K. Simmons), whom Rod thinks Peter resembles.
Peter and Kyle head off to find Roland. While outside his house, Roland approaches them with a gun, thinking they are burglars. He drops it when the guys mention Helen. Roland invites them inside with his wife (June Squibb). When the guys mention they might be his sons, Roland goes into the kitchen and goes nuts at the thought of being their dad. After calming down, Roland goes to the guys and asks them for help with something.
The three go to the home of a wealthy neighbor because Roland wants to steal his Ferrari. The man and his wife go outside to see this happening, and Roland runs off to leave Peter and Kyle. However, Roland has a change of heart and goes back for them, only to get hit when the guys actually try to make off with the Ferrari.
The guys take Roland to the hospital. The doctors tell them that after a blood transfusion, they found that Roland's blood type does not match the guys, meaning he can't be their father. The guys go into Roland's room to apologize for what happened. He tells them he realized he couldn't be their father because around the time that they were conceived, he was in jail after another one of Helen's boyfriends, "Sparkly P", ratted Roland out for possessing cocaine. The guys figure Sparkly P could be their real dad.
While driving to find the man, the guys encounter a hitchhiker (Katt Williams). They pick him up and head to the man's destination, only for their car to get stranded in the middle of nowhere at night. Peter and Kyle start to argue, with Peter resenting Kyle for why he thinks his life sucks. Moments later, a train starts to approach, and they are sitting on the train tracks. Peter gets the hitchhiker out, but Kyle is stuck in the car. The train collides with the car, and Peter fears that Kyle is dead until he emerges from the distance and runs to Peter. They hug until Kyle punches Peter in the face for leaving him there.
The police and medics arrive to tend to the guys. Kyle mentions to Peter that he has been dropped by the hot sauce company and is being replaced by a dog. After the cops clear the guys to go home, Peter mentions Sparkly P, and the cops recognize that name because Sparkly P, better known as Patrick O'Callaghan, was a former respected cop. One of the cops gives the guys his last known address for them to find him.
The guys stop at a hotel for the night. Peter goes to the bar and sees a crying woman named Sarah (Katie Aselton). He approaches her and starts up a conversation. She finds him charming, and the two later go to her room to have sex.
In the morning, the guys head over to the O'Callaghan house to see a party going on. However, they soon find out it's a wake, as Patrick is dead. The guys are disappointed to find out that their potential dad is gone. Patrick's daughter goes up to make a speech, and Peter is mortified to see that it's Sarah, leading him to believe he slept with his sister. He runs out of the house, accidentally spilling a drink on one of Patrick's son's girlfriends. The sons start to fight Peter and Kyle outside until Patrick's twin brother Kevin (Jack McGee) comes out to break things up. The guys mention they are Helen's sons, and Kevin sends everyone else inside to sort things out. After sitting Peter, Kyle, and Patrick's children together, Kevin says that Patrick could not have been the guys' father, because he and Helen never had sex. They were to marry, and Patrick wanted to consummate afterwards, but she ran off with the man she truly loved, Walter Tinkler (Christopher Walken).
Peter and Kyle go to find Walter, who is a doctor and actually lives closer to their home. When Walter sees them and learns whose kids they are, he tries to run for it until Kyle hits him with a tranquilizer dart.
Helen arrives after hearing what's been happening. She finally confesses the truth to Peter and Kyle - she was never their biological mother. The guys' true mother was a young woman who Helen met when she worked at a clinic when the woman was six months pregnant with the boys. She went into labor early, and Helen managed to help her deliver Peter and Kyle, but their mother did not survive. Helen started the adoption process, and while Walter was in love with her, he couldn't uproot his life for someone else's babies. Although Kyle feels frustrated at this revelation at first, Peter comforts him with the fact that they were still raised by a great lady like Helen. The guys then hug Helen.
Peter and Kyle part ways at the airport more amicably than they have been before.
One year later, Peter is in Hawaii with Ethan, who now respects his dad more, and Sarah, whom Peter is dating. Kyle and Helen are also there with Kyle's twin children. It is also revealed that Peter and Kyle have launched their own app for users to receive helpful messages from the universe, which are recorded by none other than the hitchhiker.
*CUT TO THE CHASE*
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Twins Peter and Kyle Reynolds learn from their mother Helen that their father, once believed to be dead, may actually still be out there. They embark on a trip to go find the man. Among their potential fathers are Terry Bradshaw, a crook named Roland, a former cop named Patrick, and a doctor named Walter. None of them turn out to be their father.
Helen reveals to the guys that she is not their biological mother, as their real mother died after giving birth, and Helen adopted them. The guys decide it doesn't matter because they love Helen as their mother.
A year later, Peter is dating another woman named Sarah, and he is on better terms with his son and Kyle. Kyle has twins also and has launched an app with Peter.
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