When the Italian government relaxes the rules on gene therapy, Professor Matteo Rossi seizes the chance to make a name for himself by opening a laboratory in the shadow of the Vatican, prompting a rare letter of condemnation from the Pope. The international press descends on Rome to witness the fight between science and religion, bringing with it reporter Lorenzo L'Oscuro, fresh out of journalism school and like Rossi out to earn himself a reputation.

Away from the media spotlight Rossi is seeking answers to questions from his past in the form of a family heirloom: an unopened casket made of tarnished silver. When the casket is stolen, Lorenzo is tasked with identifying the thief by the Vatican's Cardinal Sanchez, who believes the casket will cleanse the past sins that have prevented him from ascending to the Papacy.

Lorenzo's quest brings him into contact with the mysterious Serafino who always seems to know more than he lets on. Serafino guides the young reporter through the parallel worlds of the lost casket and Rossi's experiments until he meets Madama Lucrezia - a gypsy queen of the Roman underworld who inspires Lorenzo to write an article about the plight of the Roma being forced out of the Eternal City. The very mention of Lucrezia in a newspaper is enough to awaken her adversary shielded by the walls of the Vatican, and without knowing it Lorenzo breaks the stalemate in a decades-old war for control of the streets of Rome.

With Serafino helping him to navigate the feud he has inflamed, Lorenzo hunts the thief only to discover that once opened, the casket will destroy all that he considers sacred. In his search for truth and his hunger for fame Lorenzo brings the Devil to God's doorstep, crossing the threshold of the Vatican with the most evil, guilt-laden relic remaining from the time of Christ.