By the end of the Middle Ages, because of the decline of the Western Roman Empire, the south and centre of Italy, once the cradle of the Roman Empire, became much poorer than the north. Rome was destroyed to a great extent and the Papal States, a rather freely administered region, had little authority to keep peace. This is one of the reasons why the Papacy moved to Avignon in France. Italian trade routes connecting the Mediterranean allowed for a cultural exchange and enabled general development. The city-states of Italy, and their power, expanded during this period, and they became practically independent of the Holy Roman Empire.

The region of Tuscany, especially in Florence and Siena, was the heart of the Italian Renaissance, which spread to the south, with significant influence on Rome after it was rebuilt by the popes of that era. The 15th Century was the heyday of the Italian Renaissance, but at the same time was replete with foreign invasions wreaking havoc across the peninsula. Renaissance ideals spread from Florence to such neighbouring states as Siena and Lucca. Thus, Tuscan culture became the model for all northern Italian states and the dialect spoken in the region gained significance, which today is reflected in the literature of the region. In the middle of the 15th Century, Milan quickly transformed from a quiet medieval city into a centre of art and knowledge. Venice, one of the richest harbour cities in Italy, also adopted the Renaissance culture, especially its architecture. At the end of the 14th Century, the papacy returned to Rome, but the Eternal City was still poor and dilapidated in the beginning of the Renaissance. The Renaissance, as a cultural movement, was much more visible in the centuries to come. Even though Northern Italy was the most urbanised region of Europe, some 75 percent of the people still lead lives of peasants.

A number of foreign invasions, known as the Italian Wars, continued for nearly 50 years, which began with the French invasion that devastated much of Northern Italy and ended with the liberation of many city-states. The battle which caused the most damage was fought against the Spanish and German troops when invading Rome, which ended the role of the papacy as the patron of Renaissance art and architecture.

Renaissance morality and ideas first spread from Florence. Naples was conquered and ruled by the patron of art, Alfonso I, who inspired painters, poets and scholars. In Rome, the papacy was influenced and to a greater extent controlled by the rich families from the north, the Medici and the Borgias. The popes increased their power but at the same time became rather secular, as seen in a series of  'warrior popes'.

The spirit of the Renaissance was transformed in the late 15th Century, with ideals completely adopted by the ruling class and nobility. In the early Renaissance, artists were regarded as craftsmen, but later, the cream of crop wielded great power and raised much money for projects of the Renaissance, and a trade in Renaissance Art flourished. While in the first half of the Renaissance many of the leading artists were of lower- or middle-class descent, in the second half they were increasingly high-brow aristocrats.