Cal ponders whether fate has a stronger hold than free will as she reflects on her life and her family's past. She begins with an analogy of a silkworm, tracing a thread back through time to understand how her hermaphroditism was formed. She states, "The thread began on a day two hundred and fifty years ago, when the biology gods, for their own amusement, monkeyed with a gene on a baby's fifth chromosome... and my destiny fell into place."

In his review of the novel for the New Republic, James Wood notes that "Eugenides wishes to use his three-generational structure to suggest something about fate, the bequeathments of genetics, and the possibility of revolt once fate has displayed its cards." Eugenides does not give precedence to one force over the other, highlighting that both can influence human experience. Wood concludes, "the book clearly turns on this idea of destiny, and of destiny resisted, both by free will and by helpless action." For example, even though the genetic mutation passed down by Desdemona and Lefty deeply impacts Cal, her grandparents had the freedom to emigrate to the United States, just as Cal has the option of living as a man or a woman.

The tension between fate and free will is further illustrated in Cal's conflicting views on these forces. At one point, she suggests that tragedy "is something determined before you're born, something you can't escape or do anything about, no matter how hard you try." Yet, by the novel's end, she acknowledges, "free will is making a comeback. Biology gives you a brain. Life turns it into a mind."

A central theme in the novel is Cal's journey into adulthood, a path made more complex by her genetic abnormalities. At first, her growth seems typical. Her beauty as a young girl leads to acceptance among her peers. However, as puberty progresses without the expected changes, she becomes anxious about "being left behind, left out," feeling "gypped" and "cheated." Her sense of being an outsider is further highlighted by her ethnicity.

As she becomes more conscious of her differences and her attraction to girls, she feels increasingly isolated from her peers. She manages to hide her sexual feelings to a degree in a private girls' school, where "school rituals reinforced an intimate atmosphere." However, outside the classroom, her classmates are entirely focused on boys. Cal acknowledges that her "school remained militantly heterosexual." Recognizing her differences brings about deep feelings of shame. Nonetheless, she is resilient enough to resist Dr. Luce's pressure to make her fit into what is considered normal.