The Da Varano family ruled Camerino from the mid 13th century until 1539. During the rule of Giulio Cesare da Varano (1464-1502), Camerino enjoyed a flourishing period. He showed his grandeur in his military enterprises. There are indeed several fortresses at Camerino and the surrounding area: the Borgesca Fortress (Camerino), the Varano Fortress (Sfercia di Camerino) the Aiello Fortress (Castelraimondo), the Castle of Lanciano (Castelraimondo) and Beldiletto (Pievebovigliana).

The Camerino Ducal Palace is one of the most significant examples of civil architecture built by the Da Varano family, and is now home to the University. In Esanatoglia, the Varano family built a fortified residence in the fourteenth century (now the Palazzo Comunale, or Municipal Buildings). Following an earthquake in 1997, restoration work was carried out which unearthed a unique pictorial cycle of jousters on horseback.

The Da Varano family also founded religious buildings such as the Monastery of Santa Maria Nova in Camerino, which was later dedicated to St. Clare and the Temple of the Annunciation, built between 1493 and 1508 where, according to legend, a visual representation of Our Lady took refuge, fleeing from the house of a blasphemer.