Nick Shaffer (BRECKIN MEYER) is a Chicago-based lawyer who's never done anything wrong in his life, even when a friend tries to have him go see a stripper after attending a bachelor party in Las Vegas. Brothers Blaine (VINCE VIELUF) and Duane Cody (SETH GREEN), on the other hand, are consummate con artists who will try to make a buck any way possible, although they're not the brightest bunch of siblings in Sin City, a point further enhanced by Duane's recent tongue piercing making him near incomprehensible.
Vera Baker's (WHOOPI GOLDBERG) goal is clear, however, as she wants to meet her now grown daughter, Merrill Jennings (LANAI CHAPMAN), who she hasn't seen since she gave her up for adoption 27 years ago. On the other hand, Owen Templeton (CUBA GOODING JR.) is a man who doesn't want to meet anyone - in fact, he wants to lay low -- since he's a football referee who blew a coin toss and thus caused many bettors a lot of money.
Enjoying the sights and sounds of Sin City is Enrico Pollini (ROWAN ATKINSON), an Italian tourist with a bad case of narcolepsy that leaves him sound asleep, often while still standing up. Family man Randy Pear (JON LOVITZ) wishes that could happen to him as he and his wife, Bev (KATHY NAJIMY) and their two kids, Jason (BRODY SMITH) and Kimberly (JILLIAN MARIE HUBERT), have arrived in town for a little vacation, although that's what Randy thinks he needs from them.
Those various characters have nothing to do with each other until ultra wealthy casino owner Donald Sinclair (JOHN CLEESE) has them randomly selected to participate in a contest he's concocted. After they're brought together, Sinclair and his no-nonsense lawyer, Mr. Grisham (DAVE THOMAS), inform them that they've placed $2 million in a locker in Silver City, New Mexico. Giving each of them an identical key to the one locker, Sinclair informs them that the first to travel the 563 miles and open the locker gets to keep the money.
At first, the contestants don't believe any of this, but they eventually realize it's real and set off on a madcap race through the desert in hopes of becoming instant millionaires. As Nick teams up with helicopter pilot Tracy Faucet (AMY SMART) and Enrico gets a ride with organ donor driver Zack (WAYNE KNIGHT), the various participants try to make their way to the small New Mexico town, all while overcoming various obstacles and run ins with interesting people, and not realizing that Sinclair and others are using them in a wager where they're betting on who will win.