The Civic Museum houses the splendid fresco by Piero della Francesca (1420-1492 AD), \The Resurrection", as well as the "Polyptych of Mercy". In the Civic Museum, there is also a splendid painting by Luca Signorelli, as well as works by Santi di Tito, Jacopo Pontorno, and many others.

Also worth visiting is the Romanesque Cathedral, which was modified in the 16th century. Inside, there is a carved crucifix dating back to the 10th century, known as the "Holy Face" and also an important Crucifixion by Bartolomeo della Gatta.

Other churches of interest include San Francesco, Santa Maria dei Servi, Santa Maria delle Grazie, San Rocco, San Lorenzo with a suggestive painting by Rosso Fiorentino, and Sant'Antonio, which has a processional banner by Luca Signorelli. The imposing city walls were built by the Tarlati family and restored in the Renaissance period by Giuliano da Sangallo. The fortress at one corner is now a private residence.

Sansepolcro also gave birth to the painter Raffaellino del Colle (1490-1566 AD) and the painter and architect Santi di Tito (1538-1603 AD).

In 1441 AD, it became part of the territory governed by the Republic of Florence, where it remained until it was conquered by the powerful Duchy of Lorraine, whose dynasty was interrupted by the Napoleonic conquest. The Treaty of Vienna restored Sansepolcro to the Grand Duchy of Tuscany. Today, the valley thrives on tourism, woodworking, goldsmithing, and pottery. Of great importance is the economic activity of the large food industry based in Sansepolcro.