Signorelli must have been just over thirty, when he became involved in the decoration of the Sistine Chapel. Luca's name does not appear among the group of Tuscan and Umbrian artists (Cosimo Rosselli, Botticelli, Ghirlandaio and Perugino) who, on 27 October 1481, signed the contract for the decoration of the side walls of the famous chapel, which were to be frescoed with Biblical scenes. But Vasari is absolutely certain of his involvement and his hand is evident in some details of the huge scene of Moses's Testament and Death. The painting, at any rate as it appears to us today, is for the most part the work of Bartolomeo della Gatta , reflecting his typical use of vibrant colour and subtle lighting. But, amidst the numerous figures that populate the scene, there are some whose anatomical description is full of energy and who convey powerful emotions: the young nude seated in the centre, for example, or the two clothed figures portrayed with their backs to the onlooker, or the man with the stick leaning against Moses's throne. Luca Signorelli's hand appears quite obvious in these details, and in others as well.
 In 1508 Pope Julius II summoned artists to Rome, including Signorelli, Perugino, Pinturicchio and Il Sodoma to paint the large rooms in the Vatican Palace. They began work, but soon the pope dismissed all to make way for Raphael. Their work was taken down, except for the ceiling in the Stanza della Segnatura. Luca returned to Siena, but mostly lived in his hometown of Cortona. He constantly was at work, but the performances of his closing years were not of the quality of his works from 1490–1505.
 Bartolomeo della Gatta (1448-1502), born Pietro di Antonio Dei, was an Italian (Florentine) painter, illuminator, and architect. He was the son of a goldsmith. He was a colleague of Fra Bartolommeo. In 1468, Bartolomeo became a monk in the Order of Camaldoli, probably in the Church of Santa Maria degli Angeli in Florence, which his brother Nicolo had already entered. Upon taking holy orders, he changed his name to Bartolomeo. About 1481, he was summoned to Rome where he contributed to the cycle of frescos on the walls of the Sistine Chapel. Bartolomeo eventually became Abbot of San Clemente in Arezzo. He died in 1502 and was buried in the Abbey of San Clemente
Luca Signorelli was born as Luca d'Egidio di Ventura in Cortona, Tuscany (some sources call him Luca da Cortona). The precise date of his birth is uncertain; he is said to have died at age of eighty-two, and birth dates of 1441-5 are proposed. He belongs to the Tuscan school, although he is also associated with that of Umbria.
His first impressions of art seem to be due to Perugia — the style of Bonfigli, Fiorenzo and Pinturicchio. Lazzaro Vasari, the great-grandfather of art historian Giorgio Vasari, was brother to Luca's mother; he got Luca apprenticed to Piero de Franceschi. In 1472 the young man was painting at Arezzo, and in 1474 at Città di Castello. He presented to Lorenzo de Medici a picture which is probably the one named the School of Pan, discovered in Florence and formerly in Berlin (destroyed during the Second World War); it is almost the same subject which he painted also on the wall of the Petrucci palace in Siena — the principal figures being Pan himself, Olympus, Echo, a man reclining on the ground and two listening shepherds.
He executed, moreover, various sacred pictures, showing a study of Botticelli and Lippo Lippi. Pope Sixtus IV commissioned Signorelli to paint some frescoes, now mostly very dim, in the shrine of Loreto — Angels, Doctors of the Church, Evangelists, Apostles, the Incredulity of Thomas and the Conversion of St Paul. He also executed a single fresco in the Sistine Chapel in Rome, the Acts of Moses; another, Moses and Zipporah, which has been usually ascribed to Signorelli, is now recognized as the work of Perugino.
Luca may have stayed in Rome from 1478-1484. In the latter year he returned to his native Cortona, which remained from this time his home. In the convent of Chiusuri (Sienna), he painted eight frescoes, forming part of a vast series of the life of St Benedict; they are at present much injured. In the palace of Pandolfo Petrucci he worked upon various classic or mythological subjects, including the School of Pan already mentioned.
From Siena he went to Orvieto, and produced his masterpiece. These are the frescoes in the chapel of S. Brizio, in the cathedral, which already contained some pictures on the vaulting by Fra Angelico, who had begun the murals fifty years earlier. The works of Signorelli represent the events leading up to the Last Judgment, with the Pomp and the Fall of Antichrist, and the Eternal Destiny of Man, and occupy three vast lunettes, each of them a single picture. In one of them, Antichrist, after his portents and impious glories, falls headlong from the sky, crashing down into an innumerable crowd of men and women. Paradise, the Elect and the Condemned, Hell, the Resurrection of the Dead, and the Destruction of the Reprobate follow in other compartments. To Angelico's ceiling Signorelli added a section showing figures blowing trumpets, etc.; and in another ceiling he depicted the Madonna, Doctors of the Church, Patriarchs and Martyrs. There is also a great deal of subsidiary work connected with Dante, and with the poets and legends of antiquity. Other murals in the chapel depict the Doctors of the Church and Martyrs of the Church, an explicit reference to two important Orvietan martyrs in the centuries preceding the execution of the lunette paintings.
The daring and terrible inventions, with their powerful treatment of the nude and arduous foreshortenings, were striking in its day. Michelangelo is claimed to have borrowed, in his own fresco at the Sistine Chapel wall, some of Signorelli's figures or combinations.
The contract for his work is still on record. He undertook on April 5, 1499 to complete the ceiling for 200 ducats, and to paint the walls for 600, along with lodging, and in every month two measures of wine and two quarters of corn. Signorelli's first stay in Orvieto lasted not more than two years. In 1502 he returned to Cortona, and painted a dead Christ, with the Marys and the martyrs Saints Parenzo and Faustino.
After finishing the frecoes at Orvieto, Signorelli was much in Siena. In 1507 he executed a great altarpiece for S. Medardo at Arcevia in the Marche, the Madonna and Child, with the Massacre of the Innocents and other episodes.
In 1508 Pope Julius II determined to readorn the camere of the Vatican Palace, and he summoned to Rome Signorelli, in company with Perugino, Pinturicchio and Bazzi (Sodoma). They began operations, but were shortly all superseded to make way for Raphael, and their work was taken down. Luca returned to Siena, living afterwards for the most part in Cortona. He continued constantly at work, but the performances of his closing years were not of special mark.
In 1520 he went with one of his pictures to Arezzo. He was partially paralysed when he began a fresco of the Baptism of Christ in the chapel of Cardinal Passerini's palace near Cortona, which (or else a "Coronation of the Virgin" at Foiano) is the last picture of his specified. Signorelli stood in great repute as a citizen. He entered the magistracy of Cortona as early as 1488, and held a leading position by 1523.
Luca Signorelli died on October 16, 1523.