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NOTE: This explanation of the value of this book is also a spoiler. So just read the book if you want the real story in amazing words and phrases. However, the book is no less beautiful and original even if you know what happens. The book contains indescribable gender-related issues.
The protaganist of this amazing, disturbing and brilliant book is Cal/Calliope, who is characterized by both male and female identities. The book begins with Cal as the narrator, who explains that he suffers from a recessive genetic condition that leads him to be born with female traits, although he later reveals that he has always possessed masculine traits as well. Cal wonders whether he saw "...through the male tricks because I was destined to scheme that way myself? Or do girls see through the tricks, too, and just pretend not to notice?"
Cal lives in the current century, and his family history, along with world-wide strife are essential to his story; eventually, there is also terrible strife within his family, with Cal and his gender identify at its center, initally only symbolically.
Cal's grandparents are brother and sister, and, when Cal's mother is pregnant with Cal, she expects a "boy" but gives birth to a "girl". At this point Cal is Calliope, known as "Callie." and is raised as a girl. No one has any idea that Callie is intersex.
At the age of 14, Callie falls in love with her best friend, a female whom Callie refers to as the "Obscure Object," and they have a sexual relationship. At this juncture, Callie also has her first sexual encounter with a man, who is the "Obscure Object['s]" brother.
A physician who treats Callie for an injury she sustains discovers that she is intersex. At a New York clinic she undergoes a series of often humiliating and frightening tests and examinations. Once she learns about her dual gender, Callie must consider the possibility of reassignment surgery; instead, she runs away and "becomes" Cal, who joins a burlesque show in San Francisco after hitchhiking across the country.
Cal learns of his father's death upon his release into his brother's custody after Cal is arrested during a police raid at the scene of the burleque show, and they go home together, returning to their family home on Middlesex. Cal's grandmother finally "sees" his condition and ends up confessing to Cal that she and his grandfather were siblings. As his father's funeral is conducted at a church, Cal plants himself in the doorway of the family's home to ensure that his father's spirit will not infiltrate the home, thereby preventing Cal from becoming the "man" of the house. Cal ultimately becomes a diplomat in a location in Berlin. There he meets a Japanese-American woman, with whom he hesitatingly enters into a relationship.
Heartbreak, confusion, prejudice (racial as well as sexual, as demonstrated by the treatment of Cal's grandfather, a Greek immigrant, by "white" people once he migrates the United States), irony, hatred, love and even some humor reign in this book; reading this book was one of the most positively incredible experiences I have ever had.