Situated on the Tiber river, it was the birthplace of the painters Piero della Francesca, Raffaellino del Colle (a pupil of Raphael) and Angiolo Tricca. It was also the birthplace of the Italian mathematician Luca Pacioli.
Economy is based on agriculture. Industry includes manufacturing, food processing and pharmaceutics. It is the home of Buitoni pasta which was founded by Giulia Buitoni in 1827.
According to the tradition, the town was founded around 1000 AD by two pilgrims (Arcanus and Aegidius), who founded here an oratory (where now is the Cathedral) during their homecoming from the Holy Land. First historical mentions are slightly later, referring the the Benedictine Abbey built in that period. The historical centre Sansepolcro reached its current size around 1400, and in 1500 received its walls by Giuliano da Sangallo. The city was ruled by the Milan, the Malatesta Family, and then by Florence.
Sansepolcro escaped artillery fire during World War 2 because the British captain charged with the task had read the essay by Aldous Huxley which described The Resurrection by Piero Della Francesca housed in the Museo Civico as "the greatest painting in the world". Captain Antony Clarke had never seen the painting but at the last moment (shelling had already begun)remembered where he had heard of Sansepolcro and ordered his men to stop. A message receieved later informed them that the Germans had already retreated from the area - the bombardment hadn't been necessary and the town, along with its famous painting survived.