Cardinal Piacenza was born in Genova on September 15, 1944.

He was ordained a Priest for Genova, Italy on December 21, 1969. On October 13, 2003, he was appointed  President of the Pontifical Commission for the Cultural Heritage of the Church and Titular Bishop of Victoriana. His ordination as Bishop took place on November 15, 2003.

On August 28, 2004 he was appointed President of the Pontifical Commission for Sacred Archeology, and just a few years later, on May 7, 2007, he was appointed Secretary of the Congregation for the Clergy and Titular Archbishop of Victoriana. He was appointed Prefect of the Congregation for the Clergy on October 7, 2010.

On February 28, 2013 he ceased his role as Prefect of the Congregation for the Clergy upon the retirement of Pope Benedict XVI.

On November 20, 2010 he was elevated to Cardinal and appointed Cardinal-Deacon of San Paolo alle Tre Fontane. He was installed on April 2, 2011.