The 16th century is marked by the spread of the cultural movement of the Renaissance. This period is characterized, throughout Italy, by the general renewal of all the arts. The wealthy families who ruled the cities competed with each others to assure the best artists to magnify their courts. One of the most famous and generous family were the Medici, the ruler of Florence, who gathered around their court the best sculptures, poets, architects, and genial minds of their period. In Rome it was the pope who assumed the role of artistic Maecenas.

The restoration of the city and the first steps towards the re-establishing of the papacy supremacy over Rome and central Italy began in 1420, with Pope Martin V, a member of the important and rich Roman family. Soon the supremacy of the pope was recognised by the Commune self, and the cuty acknowledged its dependency on the papacy. Once re-established the pontifical monarchy, in 1447, Rome underwent a period of restoration and enrichment.
During the papacy of Nicholas V (1447-1455) the defence walls were repaired, palaces built, and churches restored. He carried out work at Saint Peter's and the Vatican--where he established his residence--and strengthened his fortifications of Castel Sant'Anglelo. He restored also the administrative offices of the Commune on the Capitoline Hill, and, under the guidance of Leon Battista Alberti, recognised the importance of preserving the buildings of ancient Rome. Under a massive papal patronage, Rome rescued large part of its ancient prestige and artistic beauty. Popes called to the city the major artists, whose works, at the end of the century, made Rome the primary focal point of the Renaissance.

On of the richest patrons of his time was Sixtus IV, a member of Della Rovere family. In 1471 he founded the oldest public art collection in the world when he donated to the city the sculptures which now form the nucleus of the Capitoline museums, and he considerably increased the holdings of the Vatican library and made it public. He rebuilt the 'Sistine' Chapel (named after him) and constructed the Ponte Sisto across the Tiber.
He also reorganized the streets of the city. In the meanwhile, his nephew Cardinal Raffaello Riario commissioned the erection of the splendid Renaissance Palazzo della Cancelleria, the grandest of all the wealthy cardinals' residences of that time. But Rome became the real centre of the High Renaissance at the beginning of the 16th century, under the papacy of Julius II, who spent untold riches on ambitious artistic projects designed to glorify the papacy as successor to the ancient Roman Empire.

Thanks to this papal patronage some of the best artists of the time were commissioned to honour and celebrate the glory of those popes who financed their works. Michelangelo, Donato Bramante, Raphael, and other artists contributed to embellish and give a new splendour and grandeur to Rome. In this period, the construction of the new Saint Peter's Basilica progressed, even if it was only under Pope Sixtus V (1585-1590) that the dense, confused, medieval urban pattern began to be modernized.
After Clement VII took sides with Francis I of France against the emperor Charles V, German mercenary troops captured Rome in the devasting Sack of Rome in 1527, with great damage for the city. Roman population fell to around 30,000 inhabitants and Rome lost its prestige as a centre of humanism The humiliation of the pope (obliged to take refuge in Castel Sant'Angelo) and the attack of Martin Luther –who had visited Rome in 1511- preluded the period of the Counter-Reformation.

In order to re-establish the grandeur of the Catholic Church, the Farnese Pope Paul III named Rome 'the Holy City' and proceeded to a great work of rennovation. Among the many beautiful constructions of his time, the pope also commissioned the splendid Palazzo Farnese, perhaps the most dignified and impressive palace in Rome. He also approved the founding of the order of the Jesuits in 1540, which led to the erection of the great Jesuit church of the Gesù.

Pope Sixtus V did more than any other popes to celebrate and glorify the Catholic Church. His great work of renovation and construction had a great effect not only on the Vatican, but also on all the city of Rome. Three major streets were laid out to radiate from Piazza del Popolo to the centre of the city. Sixtus also commissioned the construction of many squares and fountains, and he restored the Acqua Felice aqueduct. Besides, old churches were refurbished, and Saint Peter's dome was completed.
Under his papacy, the district of the Borgo between the Vatican and Castel Sant'Angelo was formally incorporated into the city of Rome in 1586. By then the population of the city was around 100,000 and Rome became the most cosmopolitan of its time.