In Texas, a man hears a news report about a new designer drug called Crystal Dream, highly addictive and administered by rubbing small amounts in the eyes. He leaves a woman he'd shacked up with and rides across the American Southwest region, avoiding major highways & staying on a route that runs parallel to the Mexican border. He arrives in Los Angeles and stops at a gas station convenience store to buy cigarettes. The store is being held up, but the man pays no attention and tries to buy his cigarettes anyway. When threatened by one of the robbers, he disarms and beats up the thug and his cohorts quite easily. When asked by the cashier what his name is, he replies "Harley Davidson" and leaves with one of the pistols used in the robbery, a Desert Eagle.Harley goes to a bar where he happens on an intense pool game between his best friend, The Marlboro Man, and a hulking man. Marlboro's opponent is convinced that Marlboro cheated to win and a fight breaks out. Marlboro is able to beat the man and sarcastically thanks his old friend for not helping.Harley and Marlboro go to their old haunt, the Rock N' Roll Bar & Grille, near Burbank. Harley finds out that the city of Burbank has been turned into a giant international airport. Inside, they find their old friends, still working at the bar and still running scams. Their biggest friend, Jack Daniels, works with Jimmy and takes falls in arm-wrestling matches to cheat contenders and bettors out of their money. Jack immediately starts a fight with Harley, who'd had an affair with Jack's then girlfriend, Lulu, now a singer in the bar and married to Jack. The bar is still run by the same man, whom everyone calls "Old Man", however, the bar has fallen on hard times and is being threatened with foreclosure by the Great Trust Bank, that wants to construct a skyscraper on the land. Jim tells them that Jack has been taking falls to raise enough money to save the bar for the Old Man. Harley and Marlboro both convince their old friends to rob an armored car belonging to Great Trust to get the funds to save the place.The next day the guys set up an elaborate system of construction detours for the armored car, leading it to a mostly-secluded side street, where they tie up the drivers and steal the sacks in the back. The load the sacks into a pickup truck waiting in the sewer line below the street. The guards warn them that they're in way over their heads. Just then a large limousine pulls up and several men dressed in black leather overcoats get out and begin firing on the robbers. They seem impervious to the shots fired back at them and continue a relentless assault, advancing steadily. Jack suddenly shows up, riding his own motorcycle; he removes the cap on the gas tank and jumps off, letting the cycle slide towards their attackers. He lights the line of fuel on fire, igniting the bike, however, the attackers simply jump over it and continue towards them. The gang manages to load the last of the loot into the truck and they escape. Later, while examining the bags they stole, they find small, clear blue bars instead of money; it is the illegal narcotic, Crystal Dream.The leader of the team of assassins, Alexander, meets with the CEO of the Great Trust Bank, Chance Wilder. Wilder inquires about those who stole his merchandise. Alexander believes them to be small-time crooks who stumbled upon a big score. Wilder orders Alexander to track them down and kill them and retrieve the drugs.That night, after flipping off a motorcycle cop and some reckless riding, Marlboro is pulled over. The cop turns out to be his former lover, Virginia. The two spend the night together and in the morning Marlboro finds out she's engaged. Harley shows up and takes Virginia out to breakfast. During their conversation, the subject of Crystal Dream comes up. Virginia tells Harley that it's 100% addictive and causes neurological damage and eventually death. When they return to Virginia's house, Marlboro is already up and repairing his boots with duct tape, fuming about Virginia's new marriage. He decides to steal her fiance's Harley-Davidson motorcycle.Harley and Marlboro go to the headquarters of the Great Trust and talk to Wilder via telephone. They demand $2.5 million for the dope they stole, plus one more dollar for a side bet between them. Wilder agrees to have someone meet them that night in the airplane graveyard for the exchange. Alexander shows up with the money and the transfer goes off without any problems. That night, while they hang out in the bar's back room celebrating, Marlboro is suspicious of the ease of the exchange. Suddenly, Alexander and his men show up. Watching through a one-way mirror, the Old Man tries to convince them that the gang isn't there. Their leader appears to walk away as if to leave and suddenly turns around and shoots the Old Man. They open fire on the room behind the mirror; Harley and Marlboro are the only ones who escape alive by jumping out the window; Jimmy, Jack and Jose are all killed.The two retreat to the nearby airport and hide in the baggage compartment of a plane. One of the mysterious assassins nearly finds them but they escape to Las Vegas. They check into an expensive hotel. However, they are tracked to Vegas by Alexander. The two escape to the hotel's roof and jump off into the swimming pool. Harley finds out that they've been tracked with a device hidden in the dollar coin given to them by Alexander. The two hop a freight train headed east after deactivating the tracker, but Marlboro leaves after telling Harley that they owe it to the dead friends that helped them to go back to LA and settle things. Harley refuses to go and Marlboro jumps off train. Harley later catches up with Marlboro and they form a plan to meet with Alexander, reactivating the tracker in the coin.Alexander traces them to the airplane graveyard, finding the briefcase that contained the money but only finding the dollar coin inside. However, he sights Harley and Marlboro nearby and a gunfight ensues. Marlboro is able to kill both of Alexander's two remaining men by hitting them in the head, however, Alexander catches Marlboro and holds him hostage. Harley, never a very good shot to begin with, tries to shoot Alexander and misses, hitting Marlboro. Harley finally summons up the aim to hit Alexander and he and Harley finally kill him.Alexander's helicopter pilot takes them to Chance Wilder's office. They give Wilder his money back and demand he change the lease on the Old Man's place. Wilder is unwilling to do so and orders his men to kill them when the pilot, paid off by Harley and Marlboro, appears hovering in his chopper outside. He opens fire on the office with the chopper's cannon, killing Wilder's thugs. Wilder insults Marlboro's dead father; Marlboro begins to beat him up until Wilder dangles out the window of his office, holding onto Marlboro's disintegrating cowboy boot. Harley helps him out, the boot comes apart and Wilder falls to the street.Marlboro and Harley part ways at a rodeo, where Marlboro is riding a bull. As Harley rides away, he picks up a beautiful hitchhiking woman.