Leslie Mann and John Lithgow play daughter and father, respectively, in this movie. They played a married couple in the movie Orange County.
During the scene when Paul Rudd's character Pete is having coffee with his friend Barry, they are talking about why Pete told Debbie about taking the Viagra. There is a song playing in the background, "Magnet and Steel" by Walter Egan. This song was also in "Overnight Delivery" with Paul Rudd. It was Paul Rudd's character (Wyatt Tripps) and Kimberly Jasney's love song.
Mark E Everett from the rock band 'Eels' filmed a cameo which was cut from the film.
Pete (Paul Rudd) makes a joke comparing his sexual prowess to that of David Schwimmer (and Ross, Schwimmer's character from "Friends") in a way that makes it clear that he thinks that neither Pete nor Schwimmer are very good in bed. A spokeswoman for Schwimmer told the Chicago Sun-Times newspaper that Schwimmer was not asked beforehand if he would be okay with being the butt of that joke, but Judd Apatow clarified that he didn't mean anything insulting by it; just that Schwimmer is an example of a famous person who is more like Apatow. Paul Rudd was a regular guest star on "Friends" during the show's last two seasons.
The two girls playing Pete's & Debbie's children are actually the daughters of Leslie Mann & Judd Apatow.
Sadie is a big fan of Lost and Jack (Matthew Fox) is repeatedly shown on screen. In Knocked Up (2007), Ben is very disparaging about Matthew Fox, saying there is nothing interesting about him. Ironically, Paul Rudd was a self-described "mega-fan" of "Lost" when it was on the air.
Billie Joe Armstrong from Green Day makes a cameo in which he mentions that it's a pretty big deal when Glee buys a song. "Good Riddance" by Green Day was purchased by Glee but never aired.
The main characters from "Knocked Up", Ben (Seth Rogen) and Alison (Katherine Heigl), do not appear in this "sort-of sequel", but references to both characters are made: A picture of Alison can be seen on the wall and Pete plays Scrabble on his iPad with Ben and later mentions getting marijuana cookies from Ben. Three other, more minor characters from Knocked Up, do appear in this movie as well: Charlyne Yi's character Jodi (an amiable stoner in Knocked up; now an employee in Debbie's store), Jason Segel's character Jason (one of Ben's best friends with a crush on Debbie in Knocked Up; now Debbie's personal trainer) and Tim Bagley reprises his role as OB/GYN Dr. Pellagrino.
According to Judd Apatow on the DVD commentary, the man who Megan Fox hooks up with at the store is played by Bill Hader.