John Beckwith (OWEN WILSON) and Jeremy Grey (VINCE VAUGHN) have known each other for years, both as business partners -- working as divorce mediators -- as well as social friends where their favorite pastime is crashing weddings. They don't do so for the food or drink -- although they partake in both -- but instead attend the ceremonies -- with fake names and occupations -- to meet and bed as many ladies as possible.
After a busy, several-week season of that, John is ready to take a break, but Jeremy is all set for the "Kentucky Derby" of weddings in the Washington, DC area where Secretary of the Treasury William Cleary (CHRISTOPHER WALKEN) is set to give away his oldest daughter in marriage. Being seasoned pros, the two have no problem crashing and then fitting into the ceremony and reception where both set their sights on the Secretary's other daughters. For Jeremy that's Gloria (ISLA FISHER) who he easily deflowers on the beach, while John has set his sights on her older sister Claire (RACHEL MCADAMS).
When Jeremy realizes he has a clingy and then seemingly psychotic young woman on his hands, he wants to leave, but Gloria convinces her dad to invite him and John back to their shore compound. That suits John just fine as he's still after Claire despite discovering that she has a preppy and aggressive boyfriend in the form of Sack Lodge (BRADLEY COOPER).
Once at the getaway, the two men discover they're in over their heads, what with the family's grandma (ELLEN ALBERTINI DOW) cursing like a sailor; Sack's brutal touch football play; the Secretary's wife, Kathleen (JANE SEYMOUR), coming on to John; and her troubled gay artist son, Todd (KEIR O'DONNELL) coming on to Jeremy when Gloria isn't.
As Sack tries to figure out the truth concerning them, John and Jeremy experience developments, complications and feelings for others that they never could or would have imagined might occur.