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.

On their way through the "bible-belt", in Weneville, Texas, they stop to get some food. They pull in to a Jesus-themed restaurant, and Gary and the waitress become smitten with each other. In hilarious sit-com fashion, he fails every time to notice that she has a mole that covers half her face, but Mike sure does...until Gary goes to her house to meet her. Meanwhile, Mike tries to win a Hotrod in a "hands on the Hotrod" contest.

The boy duo now find themselves at a Phish concert in Vermont where Gary accidentally swallows 4 hits of acid. When he comes to his senses, he discovers he's married to a 35-year-old hippie woman with three kids. Meanwhile, Mike discovers the secret evil behind the bands unwarranted success.

Gary and Mike go on MTV's Road Rage (a play on Road Rules) and visit Mike's brother, Ben in Santa Fe, New Mexico. Ben gets jealous of Mike because he becomes more popular than him, and Gary meets a new "friend". WWF wrestler Chyna makes a guest appearance and falls in love with Gary's new "friend" at the end of the episode. Officer Dick catches up with Ben, whom he assumes is Mike under an assumed identity, and shoots out the tires of his SUV which he won at the end of the Road Rage program.

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.

It's Viva Las Vegas for Gary and Mike, when Mike sets up a plan to help Gary get rid of his "virginitis" by setting an unknowing Gary up with an escort. Gary thinks the girl really likes him and winds up falling for her hard. Meanwhile Mike is counting cards in the casino owned by the same honked-off mobsters who gave them their hotel room, as his source of income.

Gary and Mike are in The Big Apple Now, but just their luck their car gets stolen. So Gary and Mike decide to disguise themselves like Jewish people and go to a Britz. Some other Jewish people chase them away all the way down in to the subway. Gary and Mike have a fight and separate, and Gary becomes one of the "Mole People" who live in the sewers while Mike seems to luck out at every turn from being handed $50 dollars by a kind blind man, to getting to model with European supermodels, to bedding with them. Presumably after they reunite and reconcile, they would head to Atlantic City, New Jersey as mentioned. However this is not made into an episode.

In Minnesota, as Hasselhoff's comet nears, Gary and Mike meet up with two girls whom turn out to be part of a cult. Gary wants to get out of there quick, but Mike says he's to close to getting some to leave, so Gary reluctantly agrees to stay the night. Soon, Gary is pulled into the cult with his new name: Ga. Now it is up to Mike, whose cult name is Huh, to save Gary in time.

While making their way to Chicago, Illinois, Gary has the inside of his mouth stung by a bee and is rushed to a hospital. After a close call with death, Gary soon decides he should come clean with his father about his road trip with his buddy Mike and breaks the news to him on a special Father's Day episode of "Jerry Springer".

After traveling from Miami, Florida to Portland, Oregon, the duo discover Mike's ex, Beth, who has been seen as RazorKat's drummer, is getting married in Miami, prompting Mike to drive all the way back. Mike doesn't like the guy, whom seems to have everything. Thanks to some books about a John Shaft knock-off, Gerald Stroke, Gary is acting emulous in a Shaft-like manner, and helps Mike figure out what Beth's finance is really about, as Mike attempts to sort out his feelings for her.

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

Between Minneapolis and St. Paul, Minnesota, the duo make their way to the Mall of North America (a take-off of Mall of America) to spend a large amount of coupons to support themselves for the whole winter...only to discover that the coupons have expired. Through the kindness of a stranger, Gary and Mike get a job at Corn Diggity Dog in the Mall. A competitor corn dog company is putting Corn Diggity Dog out of business until Gary realizes he can save the business by winning a trick Corn Dog competition.

In San Francisco, California Officer Dick finally manages to catch up with the bumbling duo again, and pursues them in a high speed chase. However, like his last two attempts, his efforts would end in vain. After Dick lands into a men's club, both of them run over a speed-bump, causing Mike to spill his Slurpee on the Marine Corps flag Gary bought for his dad, as well as his shirt. Mike then prompts Gary to take off his shirt and dry it off in the breeze along with the flag. Little do the two of them know that they are driving in front of a Gay Pride Parade on national television which Mr. Newton sees, and mistakenly assumes that Gary is gay and Mike is his partner. After Gary's dad signs him up for the Marines, he goes to a strip club and meets a mysterious stranger who tells him he will kill Gary's dad; if Gary kills the stranger's wife, he will take care of Gary's father. After the wife dies accidentally, Gary must race to save his father's life. However they end up getting chased by the Police when the stranger tells them Gary killed his wife and then him (after Gary accidentally makes himself get a lethal injection). They are then chased by the Police themselves and are cornered at an incomplete highway. Gary in turn, feeling trapped by his dad with nowhere to go but down, then tells Mike to make the suicidal jump. The episode ends when it whites out into text insighting the ultimate cliffhanger: To be continued...