He was commissioned by Pope John Paul II to assist Emmanuel Milingo, Archbishop Emeritus of Lusaka, Zambia, in returning to the Catholic Church in 2001.

He held this post until his resignation in 1995 upon being named Secretary of the Congregation for the Doctrine of the Faith under Cardinal Joseph Ratzinger, who later became Pope Benedict XVI.

Appointed Archbishop of Genoa on 10 December 2002 and installed on 2 February 2003, Bertone was elevated to the College of Cardinals in the consistory of 21 October 2003, as Cardinal-Priest of Santa Maria Ausiliatrice in Via Tuscolana.

[7] Two weeks before entering office, asked about reforms of the Roman Curia, Bertone remarked, "After almost two decades, an evaluation of how the dicasteries are organised is more than comprehensible, in order to reflect on how to make the existing structures more efficient for the mission of the Church and eventually to consider whether all of them should be maintained".

In recent years, your teaching has been a window open onto the Church and the world, which let in the rays of truth and love of God, to enlighten and warm our journey, even and especially at times when clouds gathered in the sky".

Bertone continued: "All of us have realized that it is precisely the deep love that Your Holiness has for God and the Church that prompted you to make this act, revealing that purity of mind, that strong and demanding faith, that strength of humility and meekness, along with great courage, that have marked every step of your life and your ministry".

"[citation needed] Bertone suggested in December 2006 that the Holy See "could, in future, field a team that plays at the top level, with Roma, Internazionale, Genoa and Sampdoria."

Bertone condemned this accusation as a "black legend" and "an attack on good sense and on rationality", which has "become so firmly established that even to scratch it is an arduous task".

[The Pope] sincerely regrets that certain passages of his address could have sounded offensive to the sensitivities of the Muslim faithful and should have been interpreted in a manner that in no way corresponds to his intentions.On 5 December 2006, Patriarch Alexy II of the Russian Orthodox Church accused the Holy See of an "extremely unfriendly policy" when he said that the Catholic Church was poaching converts in Orthodox lands in Russia and other ex-Soviet republics.

[22] In 2007, Bertone "blasted the media for highlighting the Vatican's views on sex while maintaining a 'deafening silence' about charity work done by thousands of Catholic organisations around the world.

"[23] He continued: "I see a fixation by some journalists on moral topics, such as abortion and homosexual unions, which are certainly important issues but absolutely do not constitute the thinking and work of the Church."

The head of one gay rights organization said that for someone of Bertone's stature "to dump the blame on homosexuals ... says a lot about the current state of desperation in the Vatican".

As the Secretary of State has direct access to the pope, and oversees the implementation and coordination of his decisions, many in the media questioned why Bertone didn't ensure that an adequate background review was conducted, particularly as it would only have required an internet search.

[35] Between November 2013 and May 2014, Bertone combined and renovated two apartments in the San Carlo Palace in Vatican City to create a single residence for himself, a secretary, and three nuns, reportedly a total of 604-square-metre (6,500 sq ft) and a roof terrace.

Bertone said he was renovating the apartment at his own expense, that it is half the size reported, and that Pope Francis telephoned him to express support when he was attacked in the press for expenditure.

[46] On 22 September, an official of the Government of the Vatican City State testified that the remodeling project for Bertone's apartment bypassed the normal competitive bidding process and was "singular" and "anomalous.

"[47] The same day, Spina testified that his immediate superior "told me there were no problems because Cardinal Bertone had clarified the situation with the Holy Father in person.

[49] The three-judge tribunal overseeing the trial later acquitted Spina and convicted Profiti of a lesser offense of abuse of office after the defense argued that the money was intended as an investment to benefit the hospital rather than Bertone's apartment.

[50] On 15 February 2018, Pope Francis ordered Vatican officials and bishops to lead simple lives and renounce any desire for power after they retired from senior positions.

A number of Vatican officials and bishops, including Bertone, had come under fire in recent years for holding on to luxuries, such as large apartments and in some cases even police escorts, after they left office.

[52] On 28 May 2019 a letter from September 2008 was published, which revealed that McCarrick told Bertone that he had slept with adult seminarians, while denying sexual relations.

[33] A few weeks after Bertone turned 80, Pope Francis named Cardinal Jean-Louis Tauran to replace him as Camerlengo of the Holy Roman Church on 20 December 2014.

I told him: Holy Father, you must bestow upon us the third volume on Jesus of Nazareth and the encyclopedia of faith, before you sign things over to Pope Francis".