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The family of Pepoli were lords of Bologna who took power in the chaotic commune riven by the struggles between Guelfs and Ghibellines and ruled during the first half of the 14th century. Their seat in the city was Palazzo Pepoli Antico, constructed by Taddeo Pepoli. The Pepoli maintained dynastic alliances through well-considered marriages: Obizzo III d'Este, Marquis of Ferrara, married Jacopa Pepoli in 1317 and the condottiero Roberto Alidosi, papal vicar and lord of Imola, was given Giacoma Pepoli.

After the happy years of the rule of Taddeo Pepoli (1337—1347), Bologna fell to the Visconti of Milan; though Cardinal Gil de Albornoz forcibly returned the city to the papal orbit in 1360, the Pepoli never regained their former civic power.

The family remained prominent landowners. Guido Pepoli was ordained cardinal by Pope Sixtus V in 1589. In the 17th century, Palazzo Pepoli Campogrande, today housing the Pinacoteca Nazionale, was constructed following designs of G.B. Albertoni and G.A. Torri.

A later member of the family, conte Carlo Pepoli, wrote Vincenzo Bellini's libretto for I Puritani and provided the lyrics for Rossini's song "La Danza". To him Giacomo Leopardi dedicated one of his canti.

The commune of Castiglione dei Pepoli in the Italian Province of Bologna still bears the family's name.