During the 16th century, the head of the family, Marcantonio, moved to Rome, where they rose in power and wealth following the election of his son Camillo as Pope Paul V in 1605.

Paul V was an unabashed nepotist, naming his brother Francesco (1556–1620) Duke of Rignano and general of the papal army, his other brother Giambattista (1554–1609) Governor of the Borgo and castellan of Castel Sant'Angelo, and his sister Ortensia's son Scipione Caffarelli (1577–1633), becoming Scipione Borghese on his adoption) a Cardinal and his adoptive son.

As an extended family, the Borghese became some of the largest landowners of the Roman Campagna, increasing their wealth by their strategic control of their properties and a concerted policy of assuming monopolies of milling grain and the rights to run inns.

His great-grandson Prince Scipione Borghese (1871–1927) was an industrialist and sportsman, remembered for participating in the 1907 Peking to Paris Race with the journalist Luigi Barzini.

His nephew Junio Valerio Borghese (1906–1974) was a Navy official under the Fascist regime and awardee of the Gold Medal of Military Valour for his commando actions during World War II.