From his grandparents' unusual courtship and exodus from Greece in the wake of Turkish Invasion, to his parents' taboo pairing, I found the stories of Cal's family very interesting, and it's a good thing too, since Cal's actual story only takes up about one-third of the book's nearly 530 pages. A lot of the reviews I read complained about this, but it didn't bother me, probably partly because I knew nothing about the book before starting it except that I liked the cover and Eugenide's previous book, The Virgin Suicides.
As you might expect, there's some pretty hosed-up stuff in the book, from some horrific violence during the escape from Greece to the dryly medical explanation of Cal's condition. His first sexual encounter, the growing sense of dread that someone will eventually learn his secret, the anticipation of when Cal himself will realize he's different—all of these combine to make the book compulsively readable.
The ending is very well done and quite affecting, and I think Middlesex probably ranks as one of the best modern novels I've read this year. If you're not too bothered by disturbing imagery and you don't mind sprawling narratives, check it out.
Edit: I'm finally caught up. Take that, Nathan.