The first time you read one of Thomas Pynchon's epics you can barely grasp the substance of the story. Each paragraph has the potential to throw you off. You flounder and sputter, your only sustenance the undeniable beauty of his style (and the odd slapstick moment).
The second time, you get a grasp for the characters; you remember their names and their roles and you recognize them when they resurface throughout the book. You get a better sense of what the longer digressions are about, and you begin to acknowledge the themes, though most of them remain obscure and difficult to integrate into the book.
On subsequent readings, however, the real joy begins. Now that you know the characters and have a better sense of the book's structure, you can pay closer attention to what it all MEANS. You stop skimming over the inscrutable bits and realize that there's something buried deep inside them. Gradually you tease out those pieces of meaning and you recognize the book as a whole. No longer distracted by confusing surface details, you understand, appreciate, and enjoy.
This is the second time I've slogged through "Mason & Dixon" and I'm very much on track. What I got out of it this time was the complexity of the characters of Charles Mason and Jeremiah Dixon, the themes of loss and regret, the division (in this case with the Mason-Dixon Line) which serves as a conduit, enclosure, and barrier, with all the attendant opportunities (the search for power, ownership, exclusivity, and -- ultimately -- civil war).
I also better understand when Pynchon is bullshitting me. Talking dogs, self-organizing automata (the Duck who searches for love, the organic perpetual-motion watch), The Ghastly Fop's endless publication, all the impossible creatures that Mason and Dixon hear about during their survey (the Black Dog, the invisible golem, the were-beaver, the Lambton Worm, assorted ghosts and spooks), and -- most significantly -- the paranoid mysteries of the Jesuits which I realize now were taken quite seriously at the time (William T. Vollmann's "Fathers and Crows" takes a more realistic look at Jesuit paranoia).
What's the book "about?" I don't know if there's any answer to that, but the Mason & Dixon wiki might be a good place to find out. Myself, I'd rather find the meaning on my own, because it's bound to be a very individual thing.
If you're looking to tackle the book, you might do well to learn a bit about the longitude problem, and reading up on the line itself (and its geography) might help you keep your head. Since the book is written in 18th century idiom and style, keep in mind that "huz" means "us" and "Phiz" means "face."