Set in a small midwest U.S. town, Mitch Weaver (Norm MacDonald) and his best friend Sam McKenna (Artie Lange) are two misfits who "don't take crap from anyone", as Sam's father, Pops McKenna (Jack Warden) taught them. While in school as young kids, they get a bully arrested for (planted) gun possession, and catch a crossing guard/pedophine kiddie-fondler in the act (with glue). As a teenager, Mitch's single mother dies and he moves in with Sam and his father. Mitch and Sam get revenge against a spiteful meter maid by planting popcorn kernels in her car radiator, and they get revenge against a neighborhood dog that chases them to having them get a homosexual German Shepherd dog to have it's way with the dog that attacks them. (Note: gay and homophobic jokes are the recurring theme throughout the movie.)
The film then cuts to their adult lives. After losing 14 jobs in three months and getting dumped by his girlfriend, Mitch moves in with Sam and Pops. As adults, Mitch and Sam still "don't take crap from anyone" when after they get beaten up and humiliated by a group of college frat guys at their local hangout bar, the guys set up the frat guys to get arrested for fighting with the police.
A little later, Pops is rushed to the hospital when he has a heart attack. Even though his heart is failing and needs a transplant, the gambling-addicted Dr. Farthing (Chevy Chase) tells Mitch and Sam that he will only raise Pops on the transplant list if he is paid an under-the-table bribe of $50,000 in three weeks. To raise the money, Mitch and Sam try to get jobs any way they can from a failed construction site job, to being payed to samble hallougenic brownies. A little later, Mitch and Sam get jobs in a movie theater with an abusive manager named Mr. Hamilton (Don Rickles), who mocks and pokes fun of the slow-witted and overweight Sam, and the wise-cracking Mitch. The guys exact their revenge by showing a premier film of "Men In Black (Who Like To Have Sex With Each Other)" a gay porn film to a packed house. The other workers congratulate them and tell them they should open their own business.
Mitch and Sam open "Dirty Work", a revenge-for-hire business. They exact increasingly lucrative reprisals for satisfied customers until they interfere with unscrupulous local property developer Travis Cole (Norm McDonald). Cole tricks them into destroying "his" apartment building, promising to pay them enough to save Pops. Afterwards, Cole reneges, revealing that he is not the owner. However, the grandmother of Mitch's new girlfriend Kathy (Howard) lives there. Unknown to Cole, Mitch's "note to self" tape recorder captures this confession.
Mitch and Sam plot their revenge on Cole, using the tape to set up an elaborate trap. Using skunks, an army of prostitutes, homeless men, a noseless friend, the brownies with hallucinogenic additives, and Sam's father, they ruin the opening night of an opera sponsored prominently by Cole. With the media present, Mitch plays back Cole's confession over the theater's sound system. Cole sees that his public image is being tarnished and agrees to pay the $50,000. In the end, Cole is punched in the stomach, arrested and jailed, his dog is raped by a skunk, and Mitch gets the girl. Dr. Farthing overcomes his gambling habit but is said to have been murdered by his angry bookies anyway.