Born in Savona, he was the son of Paolo Riario and Pope Sixtus IVs' sister, Bianca Della Rovere. Sixtus nominated him in 1471 bishop of Treviso and cardinal, and, in 1473, archbishop of Florence. He was entrusted with Sixtus' foreign policy. To reinforce the alliance between Rome and Milan, he had his brother Girolamo married to the daughter of Galeazzo Maria Sforza, Duke of Milan.