Buscemi plays Seymour, a total dork in his late 30s who collects old 78s (are there any new 78s?) and is familiar with the excruciating minutiae of various types of jazz, blues, rag and more. His day job is some sort of assistant manager at a fast-food chain's headquarters. Seymour is not a funny dork, he is a quiet, kind of cranky, kind of friendly dork.
Birch plays Enid, best friend of Rebecca, both freshly graduated from high school. They are über-hip misfits, demonstrating clear disdain at the trite graduation ceremony. Above all 
they sneer at frauds and relish in losers. They go about town (somewhere in Florida, it looks like, but no beaches whatsoever) laughing at how stupid everyone is and reveling in such oddball characters as the total metalhead, mullet sportin' acid-washed-jeans guy at the convenience store. He is a hoot.
Seymour most definitely falls into the loser category.
If you've seen Zwigoff's Crumb, a bio of graphic novelist Robert Crumb, you know that Zwigoff is adept at drawing out the pathetic, traumatized side of losers and misfits. Buscemi and Birch do a bang-up job with their roles. Ghost World seems thematically like a natural fit for Zwigoff, Buscemi and Birch that it is certain it would be a duller film if any one of these was missing. Robert Crumb is dimly in the film, in that all the drawings in Enid's notebook are by Sophie Crumb, Robert's daughter.
No, no, I'm not going to give away any more of the plot. But I will mention that Ileana Douglas is hilarious as Enid's summer school art teacher, and Bob Balaban is stupendous as her father. Both are among my favorite, most-respected actors, and their performances here are remarkable. Worth it just to see them. Scarlett Johansson, as Rebecca, seems like she is under-acting. Like maybe she hasn't really cut her teeth yet and is operating on the instructions not to over-act. She's not terrible, but the poor thing is surrounded by stellar performances from vastly more experienced actors. David Cross (Mr. Show) gets a special mention for his bit part as a loser who thinks he's cool.
The ending is quirky, a bit sudden, and perhaps what you'd expect from Zwigoff. It definitely is not a pat ending.
One last thing: stay all the way through the credits. There's an alternative
take of one scene that is worth the wait.
j.