The beginnings of Luca Signorelli, born in Cortona around 1450, are still quite nebulous, due to the unavailability of the early works cited by several documents and by Vasari's biography. His training with Piero della Francesca, however, is confirmed by several paintings that Bernard Berenson (1926) attributes to the master's early activity: the 'Madonna and Child and an angel' from the Boston Museum of Fine Arts, the fragmentary 'Saint Paul' frescoed in 1474, along with other figures that have been lost, on the Torre del Vescovo in Città di Castello, the 'Madonna and Child and angels' from the Christ Church Picture Gallery of Oxford, and the 'Madonna and Child' from the Galleria di Palazzo Cini in Venice, known as the “Madonna Villamarina”.
In the mid-1470s, however, in addition to following the road laid out by Piero della Francesca between Arezzo and Urbino, Signorelli also opened up new horizons towards Siena, attested by several receipts from the Hospital of Santa Maria della Scala from which we also learn that through the intervention of the sculptor Urbano da Cortona, rector Niccolò Ricoveri had commissioned a panel painting from him. The buyer, however, must have not liked the painting and Signorelli had to sell it on his own; indeed, its destiny is unknown. Notwithstanding, this is a precious piece of information because it testifies to Signorelli's early relations with the art milieu of Siena and, in particular, with the Hospital of Santa Maria della Scala, which was at that time engaged in remodelling the church of Santissima Annunziata. This construction site saw the involvement of various masters: in addition to Urbano da Cortona who had settled here and had taken a liking to his fellow countryman, there was also Francesco di Giorgio Martini with whom Signorelli would share many experiences in the course of his career.
In the span of about ten years Signorelli must have also painted the 'Madonna of Mercy with Saint Sebastian and Saint Bernardino of Siena' now in the Museo Diocesano of Pienza: an altarpiece that comes from the church of San Francesco and, given its subject, seems to have been commissioned as a sort of talisman to ward off the plague, perhaps downstream of the epidemic of 1478. Until now considered a mature bottega creation, this work must in truth hail from the early 1480s when Signorelli was by then well-established in the Val di Chiana area that Pienza is not far from. We can indeed note a profound dialogue with the painting of Bartolomeo della Gatta: the great master with whom Signorelli frescoed the 'Testament and Death of Moses' in the Sistine Chapel in 1482.