Born in Florence to Franceschetto Cybo and Maddalena di Lorenzo de' Medici, he was therefore grandson of both Pope Innocent VIII and Lorenzo il Magnifico. Educated at the Medici court, he was named cardinal by his uncle Pope Leo X. In 1520 he was archbishop of Genoa, and then Papal legate in Bologna.
He accumulated bishop-sees, i.e. Saint-Andrews and Edinburgh, Marseille, Aleria (Corsica) and Ventimiglia.
He had an important role in the incoronation of Emperor Charles V in Bologna in 1530.
Two years later he was sent by another Medici, pope Clement VII, to govern Florence during the absence of Duke Alessandro de' Medici. At the conclave following Clement's death, he tried to acquire the papacy, but was beat by Paul III, and subsequently he decided to return to Florence. But here his relationships with Grand Duke Cosimo I de' Medici deteriorated, and he moved again to Massa Carrara in 1540. Two years later his loyalty to the Imperial cause was prized with the title of Cardinal protector of Germany.