In October 1542, Marcantonio and Adriano Thiene began to remodel their 15th century (Quattrocento) family palace in a grandiose project, which would have occupied an entire city block of 54 x 62 metres and faced onto Vicenza's principal artery (today's Corso Palladio).

The rich, powerful and sophisticated Thiene brothers belonged to that great Italian nobility which could move with ease among Europe's most important courts; they therefore required a domestic stage adequate for the cosmopolitan expectations of their guests who might visit them.

When in 1614 the young English architect Inigo Jones visited the palace, he noted down information directly garnered from Vincenzo Scamozzi and Palma il Giovane: "this project was made by Giulio Romano and executed by Palladio".

Most probably, in fact, the original conception of the Palazzo Thiene should be attributed to the mature and expert Giulio Romano (from 1573 at the Mantuan court of the Gonzagas, with whom the Thiene enjoyed the closest rapport) and the young Palladio should be held responsible rather for the executive design and execution of the building, a role which became ever more essential after Giulio's death in 1546.

In 1552, Adriano Thiene died in France and thereafter, when Marcantonio's son Giulio became marchese of Scandiano, family interests gradually shifted to Ferrara.