At this stage the secretary was a fairly minor functionary, the papal administration being led by the Cardinal Nephew, the Pope's confidant usually taken from his family.

The imprudence of Pope Julius III in entrusting the office of Cardinal Nephew to his alleged lover Innocenzo Ciocchi Del Monte, a teenaged, virtually illiterate street urchin whom his brother had adopted a few years earlier, led to an upgrading of the Secretary's job, as the incumbent had to take over the duties the Cardinal Nephew was unfit for.

[5] In 1968, Pope Paul VI's apostolic constitution Regimini Ecclesiae Universae further enhanced the powers of the Secretary of State, placing him over all the other departments of the Roman Curia.

In 1973 Pope Paul further broadened the Secretaryship by abolishing the ancient office of Chancellor of the Holy Roman Church and merging its functions into those of the Secretary of State.

Silvio Orlando portrayed fictional Cardinal Secretary of State Voiello in the 2016 Sky Italia Sky Atlantic HBO Canal+ co-produced television series The Young Pope and the 2019 follow-up series The New Pope.