On a two-lane highway that resembles Route 28 in upstate New York (appropriate, since Cohen was born in Kingston, New York, the road’s southern terminus), 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 the clash of the killers. After a transport bus breaks down, the passengers, save for Stacia who left previously, find themselves murdered by the either of the two twisted killers, and, in one case, a woman is left to die, tied by her wrists around a tree branch and covered with barbed wire. Fascinated, Wheeler and Walker examine each others' kills. 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 slaughters a stoner punk and sexually assaults and skins his stoner girlfriend (in addition to drawing a mouth on her by using a tube of lipstick on her duct-taped mouth).
The two psychopaths clash over who will be Stacia's killer. Wheeler handcuffs and carries Stacia in tow where he then picks up Walker on the highway, who stands in front of his truck. Ready to kill her and each other, Stacia slams on the brakes and sends the two murderous men through the windshield onto the road as well as causing the truck's cab to fall on its side. Stacia unsuccessfully struggles to get Walker's gun, while the wounded Wheeler and Walker fight to determine who will kill her.
In the end, Wheeler and Walker are killed by two even more demented ambulance drivers who plan to save Stacia for later.