Alison Scott (KATHERINE HEIGL) is a single woman who's just been offered an on-air job at an entertainment-based cable TV channel. When not working, she hangs out and lives with her sister, Debbie (LESLIE MANN), her husband Pete (PAUL RUDD), and their two young kids. The couple isn't so happily married, mainly because of Debbie always complaining about Pete, so they're not exactly the best role models for Alison regarding married life.
Then again, they're worlds ahead of Ben Stone (SETH ROGEN), an unemployed slacker and pot-head who's trying to launch a website -- that lists celebrity nude scenes in movies -- with his friends Jay (JAY BARUCHEL), Jonah (JONAH HILL), Jason (JASON SEGEL), and Martin (MARTIN STARR).
One night, while out at a bar, Alison and Ben meet, drink, hit it off, and end up having a one-night stand. Eight weeks later, she discovers she's pregnant, decides to keep the baby, and contacts Ben to inform him that he's the father.
He's initially taken aback, much like his friends, but he eventually realizes the right thing to do is be the child's father, meaning he and Alison must become a couple. As their friends and family observe from the sidelines, the unlikely duo try to forge a relationship, despite their obvious differences, as her pregnancy continues.