The movie starts off with Greg Focker (Ben Stiller) in the house with his wife, Pam (Teri Polo), preparing their two children to go to school. They are the typical couple, busy with their stuff and asking each other to run errands. Their children, who are twins, have their birthday in two weeks and Greg is planning to organise a party for them in the new house, which is halfway through completion.
The next scene cuts to Jack Byrnes (Robert De Niro) sitting in his little dingy office, examining this genealogy chart. He stares at a picture of Pam's sister with her new husband on their wedding day, muttering "scumbag". Apparently, Pam's brother in law has divorced her, leading to much resentment from Jack. Midway, he suffers a heart attack and uses two open wires to defibrillate himself, managing to survive.
Now, Greg heads to work. He meets up with a pharmaceutical representative, Andi Garcia (Jessica Alba). She is beautiful, and Greg is smitten with her, going so far as to delay a meeting with an important person. She offers him an opportunity to promote a sex enhancing drug, Sustengo, which is to cure erectile dysfunction. It is suitable for heart patients as well.
Meanwhile, Greg is in the car on the phone with his mother, Roz, who now hosts a sex advice programme. We find out that his father, Bernie, is in Seville, learning the flamenco.
In the middle of dinner, Greg receives a phone call from Jack. Jack tells Greg that he had a heart attack, but to keep it a secret as he doesn't want to alarm his family, including his wife Dina, and Pam. The reason for the call is to request that in the event that Jack dies, Greg will take up the position of "Godfocker", which is to look after the entire family, in the same obsessive manner that Jack does. Greg agrees as it will put him in Jack's good books. In addition, Greg must fulfil several criteria, like having a good home, as well as putting his children in a school of academic excellence.
A friend of Greg, Kevin (Owen Wilson), comes back to Chicago. He is Pam's ex-lover. He is a spiritual sort of person, in touch with Buddhism and a whole lot of other religions. When a screw up by the workmen working on Greg's house occurs, rendering the house unusable for the party, which in response, Kevin volunteers his house grounds for the event. This is largely due to the fact that in the garden, the workmen have dug up a giant hole. (For whatever reason.) Greg attempts to fill it with sand, but an ill timed press of a button ended with him releasing the load of sand on Jack instead, literally burying him in sand.
Jack and Dina come to live with the Fockers. Greg, to suck up even more to Jack, cooks a turkey. However Jack's son, Henry, has his pet lizard loose. While Greg is carving the turkey, the lizard jumps up on the dining table and scares Jack, (He had a terrible experience with a lizard who laid eggs in his ear while he was in army. The doctor had to scrape the larvae out, stemming his fear of lizards.) who shouts, shocking Greg, whose hand jerks and cuts his other hand. This results in a lot of blood spurting about, funnily enough landing on Jack's face.
Greg comes home from work, bringing back a bag of Sustengo. He leaves it in a corner of the house.
They clean up. Somehow, Kevin has arrived in Chicago. They meet.
On the day of the presentation to the pharmaceutical company, Greg leaves the house to reach the venue by subway. This arouses Jack's suspicions and he begins to trail Greg, on the pretext of buying milk, though there is a supermarket just across where the Fockers live. Jack loses the trail and Greg arrives at the event to promote the product. It is a success, as he makes everyone laugh with stories of his obsessive father in law (Jack) and uses Jack as a case study (He has a heart problem, possible sexual difficulties?) as an example of a typical user of Sustengo. While Andi and Greg are celebrating their success, Andi encounters an ex boyfriend. She pretends that Greg is her fiance and requests that the ex boyfriend take a picture of her kissing Greg on the cheek in a passionate way. He complies, commenting on Greg's redeye in the photo.
Meanwhile, Jack and his wife are making love. To enhance the effect, Jack pops a few pills of Sustengo. However, he overdosed and is left with a permanent erection. Greg comes home to find Jack in a corner. Greg, being a nurse, has an adrenaline shot to cure the syndrome. They proceed to inject Jack's genitals with the adrenaline. They are interrupted by Henry at the same moment where they inject, and Jack screams something.
They decide to visit the elite school which Greg hopes to send his children. Naturally, the students of "Early Human School" are all very gifted. The children go for an audition, however it is clear that Samantha, the female twin is much more intellectually capable than Henry, which prompts Jack to say that Samantha has more of the Byrnes genes than Henry, who has a "double dose of Focker", indicating his mental ineptitude. Jack's low view of his son is further confirmed when Henry farts (on purpose) in front of the teacher who is conducting the test.
While playing the rock climbing wall, Henry falls and breaks his arm. The entire family goes to the hospital where they meet Andi. Jack has already googled Andi and discovers the compromising photo which he immediately suspects Greg of an affair, as she is so beautiful. Somehow, the family gets into an argument over the "Godfocker" affair, where Greg, somewhat strained, lets out that he resents Jack as Greg was never the first choice for "Godfocker". It was actually Pam's ex brother in law, who was supposedly going to succeed Jack, but as "Bobfather." He reveals to everyone that Jack suffered a heart attack. In this scene, it is shown that Jack would rather Pam divorce Greg and marry Kevin, who is rich, devoted to Pam and the kids and ideal "Godfather" material.
He then storms off to the new house that is currently being constructed to stay there for the night. Andi drives him there, but she comes back with wine and Chinese food to cheer him up. She gets drunk and wants to sleep with him, going so far as to eat Sustengo, which leaves her in some sort of sexual frenzy. She kisses him, but he rejects her advances. Unfortunately, this is witnessed by Jack, who had come to visit Greg. To him, it seems that they are carrying on the illicit affair he had earlier suspected. They exit the house and into the garden, where the large hole is situated. Greg, in an attempt to back away, falls into the pit. Andi, so drunk she is, jumps on him. Both are knocked out.
Cut to the next morning, where the Byrnes and the two Focker children are celebrating their party at Kevin's garden. They wonder whether Greg, their father, will be coming.
Meanwhile, Bernie has returned from Seville, having changed his mind about attending the children's birthday party. He goes to the new home where he finds Greg in the pit, with Andi splayed out over him. Greg climbs out of the pit and they drive to the party.
At the party, a confrontation between Greg and Jack ensues. Jack punches Greg in the face, and Greg retaliates in self defence. This is because Jack is angry that Greg supposedly cheated on Pam. The fight continues on into the ball pit, a scene reminiscent of Jaws, where Jack cannot be seen, but he is definitely in the pit, causing movement of the balls, ready to attack Greg. Then they realise that Jinxie, Jack's pet cat has Arthur, Henry's pet lizard in the mouth. Jinxie was brought over by Kevin to cheer Jack up and Arthur by Greg as a present to Henry. Halfway, Jack suffers a heart attack. Greg stops and helps him, calling for an ambulance. The paramedics bring Jack away. The two reconcile as it is discovered that Jack knows that Greg isn't lying when he says that he did not cheat on Pam with Andi, by a method of lie detection which Jack used on Greg, by pressing on Greg's carotid artery while they were fighting. They apologise and Jack calls Greg by the name with which Greg wants to be called, "Great Focker".
Fast forward 4 months and the entire family are celebrating Christmas. The Focker parents reveal that they will be moving to Chicago, which is not happily accepted by Greg, even worse when it is announced that because the Focker parents are moving to Chicago, so will the Byrnes parents.
In the end credits, Jack has just discovered Google. He googles himself and discovers that a Youtube video of Greg using him as a case study for Sustengo. Someone has remixed it into music so that it plays "Jack Byrnes" in a very techno style of music.
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