Jonathan Lethem can't be pinned down. His books can be a mish-mash of genres, including hard-boiled detectives, science fiction, superheroes, and westerns. Motherless Brooklyn is a great place to start, as it's one of his more accessible books. It's about a man with Tourette's syndrome who becomes involved in a mystery that has links to his childhood spent in an orphanage.

If you're interested in something with more of a science-fiction bent, you can't go wrong with Gun, With Occasional Music or Girl in Landscape.

The Mezzanine is a great place to start. It's his first book, and also one of his best. It doesn't really have a plot, though. It's more like a character study and observations on the little things in life. It's very similar to A Box of Matches in that way.