Since the XV century, Cortona was part of the territory administered by the Florentine Republic. After a century of economic and political calmness, the city ended up in the war between the Spanish army and Florence by enduring an attack by the Prince Filiberto d'Orange's troops in 1509. towards the half of the century, Cosimo I de' Medici decided to build the fortress of Girifalco which was completed in 1549 because he was aware of the fundamental importance to defend a town as rich and important as Cortona, which also became the base of a captainship, from a military point of view.

Yet, the Medicean influence was not limited to the fortification of the town. In effect, in the XVI century also the Florentine Renaissance throve in Cortona and numerous monuments and works of art by the Sienese architect Francesco di Giorgio Martini and by the artists Luca Signorelli and Pietro Berrettini flourished here. The works began by the Hapsburg-Lorraine, the Grand Dukes of Florence who substituted the disappeared dynasty of the Medici were more practical. They engaged in the rebuilding and the improvement of infrastructures and on reclamations works of the countryside in Cortona.
The Accademia Etrusca was born in Cortona in 1727 at the apex of the Leopoldine period. The brothers Marcello, Filippo and Ridolfino Venuti founded it and as the first research centre on the Etruscan civilization and drew the attention of the intellectuals coming from all over Europe. Among them, there was Voltaire, Winkelman, Muratori and Pallottino. This centre also cured the Italian edition of very important works such as Diderot's Encyclopaedic Dictionary.
Violence spread again at the beginning of the new century. in 1799, its inhabitants rose against the Polish militia that tried to occupy the town on Napoleon's demand. Once Cortona was given back to the Tuscan Grand Duchy, the town rebelled against it, too, and participated to the Renaissance uprisings that led to the Plebiscite of 1860. The inhabitants of Cortona settled their definitive belonging to the Unity of Italy with this vote.
The town suffered the tragedies of the two World Wars in the XX century and it commemorated its victims after both of them. After the Second World War, the town broke a vow made by its bishop since it was saved from bombardments. The bishop charged the painter Gino Severini to draw the portraits for the Station of the Cross and the mosaicist Romualdo Mattia finished them afterwards. These works expression of Cubism and Futurism in the first half of the XX century are visible by following the way that starts from the Berarda door and leads to the sanctuary of Santa Margherita.