Eugenides can't resist a shout out to Homer and The Iliad at the beginning of the book. It sets the tone for a book that has its serious and irreverent moments and hits most of the highs and lows of human emotion, just like a Greek drama should. After setting the stage, Cal takes us back to 1922, when a sister and a brother fall in love with each other because there just isn't anyone else in their little village of Bithynios. Desdemona and Lefty Stephanides flee Greece just as Turks destroy Smyrna. They marry on the ship over to the United States, despite the fact that both of them know its wrong. They eventually have two children. Their son, Milton, marries his first cousin. (Yeah, I know this is an uncomfortable line of plot and you can never really condone their actions, but Cal tells their love stories well.) Calliope is born with pseudohermaphrodism, but no one notices. He is raised as the girl everyone thinks he is. Trouble comes along when he turns fourteen and doesn't finish developing like a girl. Oh, and he falls in love with another girl from school.
Everything comes to a head when Calliope is injured and rushed to the emergency room to see a much more observant doctor than the one that delivered him. From there, Cal is sent to a specialist in New York. Middlesex is the story of people falling in love and marrying the last person they should marry. But it's also the story about how our families shape us. Gender is cultural and can overcome biology to some extent. We play the parts of boy and girl the way we're trained to play them. But underneath it all, you can't fight your genetics. Cal reflects on the fact that he never felt out of place as a girl but, because he got a late start, he feels just a little bit wrong as a man. Physically, he looks so male that he can't go back to being Calliope.
As Cal weaves his story, you can't help but wonder who you would be if you'd been raised differently. What if my parents had raised me as a male and given me trucks instead of Barbies? If they had, would I still lust after Benedict Cumberbatch and Jason Momoa? It's the nature versus nurture question, one that psychologists have debated endlessly and will probably debate into perpetuity. Eugenides spins this impossible to crack nut into a deeply moving story.