Crescenzio Sepe received after studying philosophy and theology in 1967, the sacrament of Holy Orders. After further study he obtained his doctorate in theology, canon law and philosophy. He then worked as a lecturer at the Lateran University and the Urban University, before he was sent as a diplomatic envoy to Brazil. Pope Paul VI. conferred him on June 5, 1977 the honorary title of Chaplain of His Holiness ( Monsignor ). 1987 Pope John Paul II appointed him assessor in the Secretariat of State and the President of the Commission for media questions to the Vatican.
On 1992 he was named titular Archbishop of John Paul II Gradum and secretary of the Congregation for the Clergy and donated him on 26 April of the same year, the episcopal ordination; Co-consecrators were the then Archbishop of Krakow, Cardinal Franciszek Macharski, and the then Cardinal Secretary of State Angelo Cardinal Sodano.
On 21 February 2001 he was accepted as a cardinal deacon with the title Diakonia Dio Merciful Father in the College of Cardinals.
On April 9 of that year he was appointed as Cardinal Prefect of the Congregation for the Evangelization of Peoples. In addition, he provided the task of Magnus Cancellarius the Pontifical Urban University.
Sepe took part in the Conclave 2005, in which Benedict XVI. was chosen. This appointed him on 20 May 2006 as Archbishop of Naples and elevated him to cardinal priests per hac vice. On 1 July 2006 he was enthroned as the successor of Cardinal Michele Giordano. Following the resignation of Pope Benedict XVI, Cardinal Sepe was drawn on March 4, 2013 as the assistant to the Cardinal Chamberlain (representing the cardinal priest). He was a member of three days of the Particular Congregation, which regulates child needs during the period of vacancy.