Facing financial difficulties after 1478, Lorenzo il Magnifico plundered the Popolani boys' inheritance with "forced loans".

In 1482, Lorenzo il Magnifico arranged for the marriage between the young Lorenzo di Pierfrancesco and Semiramide d'Appiani, daughter of the Appiani lord Jacopo III of Piombino, who brought not only lucrative commercial ties but also political connections (the Appiani were related by marriage to the Aragonese of Naples).

As part of the settlement in 1485, which involved outside arbitration, Lorenzo di Pierfrancesco and his brother Giovanni il Popolano received the Medici family property of Villa Cafaggiolo in the Mugello region.

Nonetheless, it was clear that Lorenzo di Pierfrancesco would have to shelve any public office or political ambitions during il Magnifico's rule.

Two years later they were exiled, but returned when King Charles VIII of France invaded Italy and Piero was ousted from Florence by a Republican government.

In 1501, Lorenzo di Pierfrancesco was suspected of a plot with Cesare Borgia to favour the latter in the conquest of the city, but the accusations were never confirmed.