On a two-lane highway, two serial killers clash in a turf war: one is named Wheeler (Michael Moriarty) who kills hitchhikers he picks up in his truck, and the other is named Walker (Warren Kole) who is a hitchhiker who murders whomever gives him a ride. Stacia (Fairuza Balk), a recently divorced woman, falls in between the battle of wits.
After a transport bus breaks down, Wheeler and Walker kill the driver and passengers — save for Stacia, who left previously. Fascinated, Wheeler and Walker examine each other's victims. Wheeler murders a woman (Laurene Landon) and hangs her body in the truck, and pistol whips and decapitates a man with the sliding door of the luggage compartment. Walker garrotes the bus driver with a dead snake, shoots a passenger, leaves another passenger to die tied by her wrists to a tree and wrapped in barbed wire (whom Wheeler finds alive and taunts), slaughters a punk, and partially skins his girlfriend before killing her.
Later, at a roadside motel, the two psychopaths play head games with each other and Stacia, clashing over who will get to kill her. As she is leaving the motel, Wheeler offers her a ride then assaults her while driving, handcuffing her to the car. He finds Walker on the highway, standing in the lane, and brakes to a stop just before hitting him. Walker accepts a ride, and the two bicker and draw their pistols, ready to kill Stacia and each other. Stacia, sitting in the middle, slams on the brakes and sends the two murderers through the windshield onto the road and causes the truck's cab to fall on its side. Stacia unsuccessfully struggles to get Wheeler's gun, while the wounded Wheeler and Walker fight to determine who will kill her as an ambulance siren sounds.
In the end, Wheeler and Walker are side by side in the ambulance, still fighting and cursing at one another. Finally, they cease and declares a truce, as Walker attempts to strike a deal with Wheeler as he points out how much fun the two off them could have with an ambulance, revealing that he still has his craft knife he used to torture the stoner's girlfriend. However, one of the EMTs rams syringes into their chests, apparently killing them both, as the new killer tells the driver that after they had eliminated their competition they plan to save Stacia (bound and gagged in an upper bunk of the ambulance) for later.