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The Calling of Saint Matthew is made up of seven interconnected short stories, each of which is set in Rome, more often than not in Rome's Centro Storico, and takes place between the morning of the devastating December 2004 South-Asian tsunami and the death of Pope John Paul II in April 2005. The stories, or chapters, cycle about these events as well as the concerns (mainly crises of character and/or faith) of the book's central characters: a Boston stocks analyst and his pregnant wife; a young Montessori teacher from British Columbia involved with a married man; a Chicago-born hostess who takes a leave from her job in Tokyo’s Ginza district; a native Roman who works as a centurion outside the Colosseum; a man from San Francisco who travels to Rome to trace the footsteps of his recently deceased daughter; a divorced New York academic facing ethical issues at her university; and a former Christian Brother who comes to the holy city to pray for his ailing step-sister and climb the steps of La Scala Santa.

Connecting these characters are several background, recurring figures, including a Roman performance artist who believes he is the reincarnation of Caravaggio, a young woman from Ferentino who plays the organetto at the foot of the Fountain of the Four Rivers in Piazza Navona, an unscrupulous German tour guide, and a former nun who has left her cloistered convent in Croatia for a life of social service in Rome. The book is also about the city of Rome itself, as each of the stories reflects, and draws its form from, the art in and religious history of one or more of Rome’s churches. In that way, each of the stories is ekphrasic.