Starting from a re-reading of archival evidence and sources of art literature, the article advances new hypotheses regarding the famous lost fresco cycle painted in 1439-1465 by Domenico Veneziano, Andrea del Castagno and Alesso Baldovinetti in the main chapel of Sant'Egidio, the main place of worship of the Florentine hospital of Santa Maria Nuova. The proposals concern the iconography and the development of the Marian programme; the thematic relationship between the frescoes and the altarpiece realized by Lorenzo Monaco in the early 1420s; the stages of the decoration and the different roles played by the three artists. From an overall analysis, it seems clear that the 15th-century decoration of the presbytery was presided over by a coherent plan, executed thanks to the shrewd management of the patrons. But who was responsible for this commission? In the wake of Ames-Lewis's study (1979), critics have tended with increasing conviction to link the cycle to the intervention of the Medici, claiming that they had taken control of the decoration of the main chapel at a time of decline of the Portinari family, the hospital's protectors and patrons of the church. Such an assumption would be corroborated by the fact that Vasari, in his Lives, recognized in the lower panels the portraits of the protagonists of a crucial event for the Medici house, namely the flight of Cosimo il Vecchio from Florence (1433). This article, however, demonstrates that Vasari's identifications – largely based on Machiavelli's Istorie fiorentine – are groundless, underlining the flimsiness of the evidence so far put forward to prove the influence of the family in the commission. It seems instead more likely that the supervision of the decoration should be assigned to the directors of the hospital, specifically to Michele di Fruosino da Panzano – who had personally promoted other architectural interventions, including the renovation of Sant'Egidio – and his successor, Iacopo di Piero.