The story involves four Princeton seniors, both friends and roommates, getting ready for graduation: Tom, Paul, Charlie and Gil.

Tom and Paul are trying to solve the mystery contained within an extremely rare, and mysterious book, the Hypnerotomachia Poliphili, which was an incunabulum published in 1499 in Venice, Italy; it is a complex allegorical work written in a modified Italian language frequently interspersed with material from other languages as well as its anonymous author's own made-up words.

Throughout the novel, he struggles between being fascinated by the book and trying to pull away from the obsession that drew a rift between his father and his mother and is now causing discord between him and his girlfriend, Katie Marchand.

The title refers to a cipher that the characters find was used to encode a hidden message in the Hypnerotomachia, which leads to a secret vault in Rome, Italy of books and art that the author, Francesco Colonna, hid to protect them from Girolamo Savonarola's bonfire of the vanities.

The book ends with Tom preparing to pack for a flight to Florence, Italy, to reunite with Paul.