The success of a first novel is a mixed blessing for authors. Acclaim, awards, a movie deal — but what to do when the interviews dry up, the paperback tour ends, and you have to begin anew? It’s enough to cause madness and despair, or at least a paralyzing case of writer’s block.

Fans of The Virgin Suicides may have worried that such a fate befell its author, Jeffrey Eugenides. After all, it’s been almost 10 years since that obsessive case study of the Lisbon sisters and the side effects of thwarted desire and adolescent yearning made its debut. Middlesex puts such fears to rest. It’s a big, comfy book that was worth the wait, spreading its 500-plus pages across the expanse of history and geography and inviting readers to enjoy the ride as narrated by Calliope/Cal Stephanides, hermaphrodite.

" I was born twice: first, as a baby girl, on a remarkably smogless Detroit day in January of 1960; and then again, as a teenage boy, in an emergency room near Petoskey, Michigan, in August of 1974. " The story unfolds from Cal’s perspective as a 41-year-old employee of the State Department who’s been posted in Berlin. The newly unified city is richly symbolic of Cal’s past identity as a divided, confused teen and the relative sense of wholeness he feels now. He even woos a woman he meets on the subway, half-fearing her reaction to his unusual anatomy, or " crocus, " which Calliope first sensed in eighth grade: " Sitting in class with a book in my lap, or riding home in a car pool, I’d feel a thaw between my legs, the soil growing moist, a rich peaty aroma rising, and then — while I pretended to memorize Latin verbs — the sudden, squirming life in the warm earth beneath my skirt. "

The humorous, affecting story of how Cal comes to accept his difference — and to " choose " his gender as man — is just part of what makes Middlesex so full of life and motion. An extensive cast of characters populates its pages, from Jimmy Zizmo (a bootlegger who reinvents himself as a Muslim minister, Farrad Mohammad) to Father Mike, a diminutive Greek Orthodox priest who baptizes Calliope and gets more than he bargained for: " From between my cherubic legs a stream of crystalline liquid shot into the air. . . . Propelled by a full bladder, it cleared the lip of the font. . . . [and] struck Father Mike right in the middle of the face. . . . In all the commotion, no one wondered about the engineering involved. "

Generation-spanning novels played out against the backdrop of history sometimes founder in their own sense of significance. As it traces the genetics of Calliope and Cal back through generations, Middlesex encompasses the Turks’ burning of Smyrna in 1922, school desegregation, Vietnam, and Watergate, but it depicts these monolithic events on a human, accessible scale. Calliope fakes her period with " Nixonian cunning, " and we experience the Detroit race riots from the seat of her bicycle as she follows a National Guard tank to her father’s diner in the heart of the city. The diner burns, but, in a prime example of Eugenides’s sly sense of humor, the insurance money launches a successful chain of family hot-dog stands.

Those hot dogs are the Stephanides family’s ticket to the upper-middle-class suburb of Grosse Pointe and all that it entails: a Cadillac trade-up every year, private girls’ school for Calliope (where she falls in love with a classmate, the Obscure Object), and a lavish home called Middlesex. A utopian vision of glass and light, Middlesex has stairway walls with peepholes that allow glimpses into other hallways, it uses pneumatic, accordion-like barriers instead of doors, and, of course, it lacks closets. The obvious relevance of its name aside, Middlesex is an apt symbol for our hero’s existence beyond society’s traditional boundaries — and the advantages that perspective affords. " Already latent inside me, " Cal reflects, " like the future 120 mph serve of a tennis prodigy, was the ability to communicate between the genders, to see not with the monovision of one sex but in the stereoscope of both. "

Although Cal has to leave home to find himself, his return to Middlesex for his father’s funeral brings the journey full circle. Middlesex, he concludes, " was still the beacon it was intended to be, . . . a place designed for a new type of human being, who would inhabit a new world. I couldn’t help feeling, of course, that that person was me, me and all the others like me. " With Middlesex, Eugenides leads us to the edge of a glimmering future where the particularities of what makes us human takes precedence over the limiting absolute of gender.