With Nicholas V (reigned from March 19, 1447) the Renaissance entered in Rome, starting a period in which Rome was to become the centre of Humanism. He was the first pope to embellish the Roman court with scholars and artists, including Lorenzo Valla and Vespasiano da Bisticci.

On September 4, 1449 Nicholas proclaimed a Jubilee for the following year, which saw a great influx of pilgrims from all Europe. The crowd was so large that in December, on Ponte Sant'Angelo, some 200 people died crushed under their feet or drowned in the Tiber. But that year the plague reappeared in the city, and Nicholas fled dishonourably.

In any case, Nicholas asserted in a stable way the temporal power of the Papacy, a power in which the Emperor was to have no part at all. In this way, the coronation and the marriage of Frederick II, Holy Roman Emperor on March 16, 1452, was more a civil ceremony. The Papacy now controlled Rome with a strong hand. A plot by Stefano Porcari, whose aim was the restoration of the Republic, was ruthlessly suppressed on January 1453. Porcari was hung together with the other plotters, Francesco Gabadeo, Pietro de Monterotondo, Battista Sciarra and Angiolo Ronconi, but the Pope gained a treacherous reputation, as when the execution was beginning he was too drunk to confirm the grace he had previously given to Sciarra and Ronconi.

He also designed urban renewal in collaboration with Leon Battista Alberti, including the construction of a new St Peter's Basilica.

Nicholas' successor Calixtus III neglected the new cultural policy of Nicholas, devoting himself instead to his greatest passion, the love for his nephews. The Tuscan Pius II, who took the reins after his death in 1458, was a great Humanist, but did little for Rome. During his reign Lorenzo Valla demonstrated that the Donation of Constantine was a forgery. Pius was the first pope to use guns, in campaign against the rebel barons Savelli in the neighbourhood of Rome, in 1461. One year later the moving to Rome of the head of the apostle St. Andrew produced a great number of pilgrims. The reign of Pope Paul II (1464-1471) was notable only for the reintroduction of the Carnival, which was to become a very popular feast in Rome in the following centuries. In the same year (1468) a plot was discovered against the pope, organized by the intellectuals of the Roman Academy founded by Pomponio Leto. The plotters were sent to Castel Sant'Angelo.

More important by far was the pontificate of Sixtus IV. In order to favour his relative Girolamo Riario, he promoted the unsuccessful Congiura dei Pazzi against the Medici of Florence (April 26, 1478) and in Rome fought the Colonna and the Orsini. The personal politics of intrigues and wars needed much money, but in spite of this Sixtus was a true patron of art in the wake of Nicholas V. He reopened the Academy and reorganized the Collegio degli Abbreviatori, and in 1471 started the construction of the Vatican Library, whose first curator was Platina. The Library was officially founded on June 15, 1475. He restored several churches, including Santa Maria del Popolo, the Aqua Virgo and the Hospital of the Holy Spirit, paved some streets and also built a famous bridge on the Tiber which still today carries his name. However, his main building project was the Sistine Chapel in the Vatican Palace. Its decoration called on some of the most renowned artists of that age, including Mino da Fiesole, Sandro Botticelli, Domenico Ghirlandaio, Pietro Perugino, Luca Signorelli and Pinturicchio, and in the 16th century Michelangelo painted it with his famous masterpiece and made it one of the most outstanding monuments of the world. Sixtus died on August 12, 1484. He is considered the first Pope-king of Rome.

Chaos, corruption and nepotism appeared in Rome under the reign of his successors, Innocent VIII and Pope Alexander VI (1492-1503). During the vacation period between the death of the former and the election of the latter there were 220 murders in the city. Alexander had to face Charles VIII of France, who invaded Italy in 1494 and entered in Rome on December 31 of that year. The Pope could only barricade himself into Castel Sant'Angelo, which had been turned into a true fortress by Antonio da Sangallo the Younger. In the end, the skilful Alexander was able to gain the support of the king, assigning his son Cesare Borgia as military counsellor for the subsequent invasion of the Kingdom of Naples. Rome was safe and, as the King directed himself southwards, the Pope again changed his position, joining the anti-French League of the Italian States which finally compelled Charles to flee to France.

The most nepotist Pope of all, Alexander favoured his ruthless son Cesare, creating for him a personal duchy out of territories of the Papal States, and banning from Rome the Orsini family, Cesare's most relentless enemy. In 1500 the city hosted a new Jubilee, but its street grew even more unsafe as, especially at night, when they were controlled by bands of lawless "bravi". Cesare himself assassinated Alfonso of Bisceglie, his sister Lucrezia's, as well as, presumably, the Pope's son, Giovanni of Gandia.

The Renaissance had a great impact on Rome's face, with works like the Piet? by Michelangelo and the frescoes of the Borgia Apartment, all made during Innocent's reign. Rome reached the highest point of splendour under Pope Julius II (1503-1513) and his successors Leo X and Clement VII, both members of the Medici family. In this twenty-years period Rome became the greatest centre of art of the world. The old St. Peter's Basilica was demolished and a new one begun. The city hosted artists like Bramante, who built the temple of San Pietro in Montorio and planned a great project to renovate the Vatican. Raphael, who in Rome became the most famous painter of Italy creating frescos in the Cappella Niccolina, the Villa Farnesina, the Raphael's Rooms, plus many other famous paintings. Michelangelo, who started the decoration of the ceiling of the Sistine Chapel and executed the famous statue of the Moses for the tomb of Julius. Rome lost in part its religious character, becoming increasingly a true Renaissance city, with a great number of popular feasts, horse races, parties, intrigues and licentious episodes. Its economy was rich, with the presence of several Tuscan bankers, including Agostino Chigi, who was a friend of Raphael and a patron of arts. Before his early death, Raphael also promoted for the first time the preservation of the ancient ruins.