Thurgood (Dave Chappelle), Scarface (Guillermo Diaz), Brian (Jim Breur) and Kenny (Harland Williams) are childhood friends who discover marijuana. They grow up together and live in an apartment in New York. During a smoke, they send Kenny to get food. Kenny sees a horse, and starts feeding it treats. The horse dies (it's apparently diabetic), and Kenny goes to jail. His bail is set at $1,000,000. The guys get a lift home by a hot Mary Jane Potman (Rachel True), and Thurgood falls in love.
Thurgood is given some medicinal marijuana by a scientist, and the guys decide to sell more of it to raise bail money. Meanwhile, Thurgood and Mary Jane go on a date, and Thurgood promises not to smoke. He fails.
The weed sales go through the roof, and many customers partake (John Stewart, Snoop Dog, Willie Nelson, Stephen Baldwin, Jeneane Garofalo, Bob Saget and others). Scarface and Brian leave their jobs to spend more time selling. Thurgood tries to stay righteous as Brian and Scarface start spending their profits. When Mary Jane breaks up with Thurgood, he promises to stop smoking.
Meanwhile, Samson, a rival drug dealer, discovers the guys and trashes their apartment. He demands a meeting with the guys and tells them to pay him half their profits. The Guy on the Couch (Steven Wright) suggests they rob the lab for weed, but get caught. Thurgood offers to set up Samson. The cops allow them to get high before the deal, and the cops get high and forget to make the bust. The guys defeat Samson's hench-women, and Brian summons the spirit of Jerry Garcia (David Bluestein) to defeat Samson.
The cops honor the deal to release Kenny, and Thurgood reunites with Mary Jane, giving up pot for good. The end.