In the classic pattern of papal nepotism, Cardinal Borghese wielded enormous power as the Pope's secretary and effective head of the Vatican government.

He became superintendent general of the Papal States, legate in Avignon, archpriest of the Lateran and Vatican basilicas, prefect of the Signature of Grace, Abbot of Subiaco and San Gregorio da Sassola on the Coelian, and librarian of the Roman Catholic Church.

He also assumed the offices of Grand Penitentiary, secretary of the Apostolic Briefs, Archbishop of Bologna, protector of Germany and the Habsburg Netherlands, of the Orders of Dominicans, Camaldolese and Olivetans, of the Shrine of Loreto and of the Swiss Guard, and numerous other ecclesiastical positions.

[citation needed] As Cardinal Nephew (an official post until it was abolished in 1692), Borghese was placed in charge of both the internal and external political affairs of the Papal States.

Contemporaries commented on the near-public scandals that resulted on occasions from Scipione's possible homosexuality, reflected in his taste for collecting art with strong homoerotic overtones.

It was enough for envy and jealousy among courtiers to utter malicious and venomous calumnies against him, which prompted cardinals and ambassadors to report to the pope that Stefano was full of loathsome vices, and that for his nephew's honour, it was necessary to banish him entirely.Scipione subsequently fell into a long and serious sickness, and only recovered when Pignatelli was allowed to come.

However, more recently published espionage reports of Giovanni Antonio Marta speak against the results of such official investigation and substantially confirm the homosexual inclinations of Cardinal Scipione.

Borghese's first work after entering the Sacred College where he studied was the building and decoration of the oratory chapels of St. Andrew and St. Sylvia beside San Gregorio Magno al Celio.

For Borghese to complete such a project declared his devotion to the city's Christian heritage, while also marking a gesture of respect for the great Church reformer of the previous generation.

The restoration of San Sebastiano fuori le mura (November 1607 – 1614), a church built under Constantine (c. 312) housing the greatest collection of relics known at the time.

Even though later generations dispersed some of his acquisitions through sales and diplomatic gifts, the works that he assembled form the core of the holdings of the Galleria Borghese, a museum housed in the villa commissioned by Scipione (1613–15) from the architect Giovanni Vasanzio.

The Satyr and Dolphin (Roman marble copy of lost Greek bronze, 4th century BCE) typifies the elegant and sensual depictions of young male figures that were prominently featured in Borghese's collection.

[8] In the following year, Raphael's Deposition was secretly removed from the Baglioni Chapel in the church of San Francesco in Perugia and transported to Rome to be given to Scipione through a papal motu proprio.

[citation needed] Borghese also greatly admired Caravaggio's naturalistic and psychologically complex later religious paintings, such as the brooding Saint John the Baptist (1605/6), which the collector acquired from the artist's estate shortly after his death, and the intense David with the Head of Goliath (1609/10), which represents the Biblical hero extending outwards a severed head with the features of the artist Borghese appropriated Caravaggio's Madonna and Child with St. Anne, a large altarpiece commissioned in 1605 for a chapel in the Basilica of Saint Peter's, but rejected by the College of Cardinals because of its earthly realism and unconventional iconography.

The culminating work in this series that Bernini created for Borghese, Apollo and Daphne (1623–1625), represents an incident popular in Italian poetry of the early seventeenth century, and ultimately derived from the Metamorphoses by the ancient Roman poet Ovid.

Bernini depicts Apollo reaching out toward the river nymph Daphne just as she is transformed into a laurel tree by her father in order to prevent her from being burned by the touch of the god of the sun.