The story begins in St. Louis, Missouri where Gary Newton is saying his last goodbyes to his patients at the nursing home before he goes to follow the Lewis and Clark trail. He tells the patients that Clark will take over and that he is not that bad, even though he is grungy. Clark walks in and surprises Gary with a band that sends the patients into shock because they are so loud. Meanwhile Mike is in bed with a girl named Nancy. When he calls her by the wrong name, she doesn't care. In the morning Nancy's mom walks in to find them. She screams to Nancy's father to hurry there. Gary's father has just giving him the speech about the importance of his trip, and how he would be dead if anything happened to the SUV. He slowly pulls out of the driveway. Mike jumps out the window and out into the front yard as Nancy's father gets a baseball bat. Nancy calls her soon to be husband to tell him the wedding is off. Her father is angry, because it is the police chief's son. That was the only way he was going to be able to move from a trooper to a desk job. Gary is surprised when Mike jumps in the car. He sees Nancy's father in the rear-view mirror, and speeds away. When Gary tells him about the trip, Mike decides he's going too. Mike asks his parents, but they are drunk and asleep so he takes it as a yes. Gary is dreaming about Lewis and Clark telling him that Mike picked up a hitchhiker while he was sleeping. When Gary wakes up, he sees a smelly hitchhiker next to him. But Mike claims the hitchhiker is harmless. Gary agrees when he hears the man's knowledge of the trail. He says he can lead them to a certain spot, so they say o.k., but when the get there, the hitchhiker robs them of their clothes, money and he takes the car. Elsewhere, the Nancy's father suits up on his motorcycle to look for Mike. So the guys sleep overnight in the woods. They kill and eat a rabbit for food. In the morning they realize they are just in a big backyard. They also find out the rabbit they ate was a little girl's pet rabbit. The little girl's mom calls the cops and they are arrested. They tell the cops about the hitchhiker. When their story checks out, they are released to a mob of reporters, but they are picked up by devil worshipers who heard about their story and sympathize with them. They jump and tumble out of the devil worshipers' truck next to an impound lot where they find the totaled SUV. Gary reflects on the fact the that "This trip went exactly as planned...and then [Mike] showed up." To make it up to him, Mike decides to reveal the hidden stash of money worth $250 in his boot to him and prompt Gary to start their own trail he would dub "the Gary and Mike trail" rather than go home and face his dad. They buy a junker for $200. They spend their other $50 to buy a new rabbit for the little girl whose rabbit they'd eaten. But as they drive away, the bunny runs under their car and is smushed. So it ends by them driving, headed for nowhere in particular away from home.

Gary and Mike enter the nation's capital, where they're in desperate need of money...so they hunt down a friend of Mike's mom. Soon, they're working on a campaign. Gary seems to be helping a great deal, but without knowing it is causing more trouble than the campaign can stand, meanwhile Mike finds himself falling for a much, much older woman who is a Supreme Court Justice.

In Hollywood, California, the guys elude an oversexed TV mother and then encounter a person who might be Gwyneth Paltrow.