On July 9, 2008, Pope Benedict XVI appointed him secretary of the Congregation (now Dicastery) for the Doctrine of the Faith. It was consecrated by Cardinal Tarcisio Bertone, who was then the secretary of State.
On July 1, 2017, he was appointed by Pope Francis as prefect of the Congregation (now Dicastery) for the Doctrine of the Faith, president of the Pontifical Commission Ecclesia Dei, of the Pontifical Biblical Commission and of the International Theological Commission.
Pope Francis himself created him a cardinal of the Catholic Church in the consistory of November 28, 2018. The cardinal participated in the 2018 and 2019 synods.