Bishop Francesco III Eroli (1500 - 40) succeeded his uncle as Bishop of Spoleto. 

Lucrezia Borgia was made Governor of Spoleto in 1499-1502.

In 1522-23, Petrone da Vallo di Ner and Girolamo (Picozzo) Brancaleoni led a coalition of neighbouring landowners in the contado against Spoleto.  Petrone killed the papal governor, Alfonso di Cardona.  In return, Severo Minervio, Captain of Spoleto, destroyed his castle and he was burnt alive.

In 1527, Imperial troops who marched by the city after the sack of Rome left it largely unmolested.  Indeed, commerce with the soldiers proved to be profitable for the city and its merchants.