Aside from the usual issues raising his young twin kids, Sam (DAISY TAHAN) and Henry (COLIN BAIOCCHI), Greg Focker (BEN STILLER) seems to have his life in order. He's nearing completion -- through the work of Randy (HARVEY KEITEL) and his construction crew -- of refurbing an old house for his new home with wife Pam (TERI POLO), while he's moved up from male nurse to supervisor at the hospital where he works.
Yet, he's concerned about money, what with Pam wanting to send the kids to the highly recommended but ultra-expensive Early Human School run by Prudence (LAURA DERN). Thus, when drug rep Andi Garcia (JESSICA ALBA) comes knocking and wants Greg to give speeches promoting her company's new erectile dysfunction drug, Sustengo, he sees potential tuition bills being made. Of course, it doesn't hurt that Andi is bubbly and drop dead gorgeous.
But Greg is most focused on the upcoming 5th birthday party celebration for his kids, all of which means Pam's parents, Jack (ROBERT DE NIRO) and Dina (BLYTHE DANNER), have already arrived, although formerly antagonistic feelings seem to have settled down between the two men.
Meanwhile, his parents are also on their way, once Roz (BARBARA STREISAND) is done with her sexual advice TV show and Bernie (DUSTIN HOFFMAN) completes his flamenco lessons in Spain. Then there's Pam's rich ex-boyfriend, Kevin Rawley (OWEN WILSON), whose recently failed marriage proposal has him returning to her for comfort.
With the party approaching, Greg must contend with that, Andi becoming ever-more friendly (and then some) toward him, and Jack becoming suspicious that Greg no longer finds Pam attractive and is looking elsewhere for company, all enhanced by a series of misunderstandings.