[8] Remains of the road have been found under the Corsia Sistina ("Sixtine lane") of the Santo Spirito hospital and under the Generalate ("Curia Generalizia") of the Jesuits.

[8] This road was used during the late Empire by emperors who, during their increasingly rare visits to the capital, after crossing the Tiber on the Pons Helius (Nero's bridge had been already demolished for defensive reasons), made their way along the route at the foot of the Janiculum to Saint Peter's tomb.

[9] In the early Middle Ages, the future Borgo Santo Spirito was a path flanked by two walls, with vegetable gardens and a few small houses, leading from the square of the old church of Santa Maria in Traspontina (almost opposite Castel Sant'Angelo) towards the old Vatican Basilica.

[11] The same did in 727 his successor Ine of Wessex who, after abdicating in favour of his relative Æthelheard, had a building built near the Tiber to house clergymen and princes from his kingdom,[12] imposing for its maintenance a tribute called Rome scot.

[17] In 1204, Innocent had Guy de Montpellier come to Rome, and entrusted the hospital, rebuilt by Marchionne Aretino, to the Order of the Holy Ghost.

[25] The latter entrusted the work to Florentine architect Baccio Pontelli; among others he designed the Corsia Sistina, a 126 m long hall with three rows of beds, flanked by a portico under which the homeless could sleep, to whom what was left over from the canteen was distributed.

[24] Due to Pontelli's work, the church was demolished, but Pope Sixtus founded a new one, Santo Spirito in Sassia, which he left unfinished.

[21] Going westwards, on the northern side lay Vicolo dell'Ospedale, near which there were the houses belonging to the Tomacelli and Migliorati families, and on the left the Via Settimiana (today's Via dei Penitenzieri) leading to Trastevere.

[29] The schola, like the others, was founded to provide shelter for Frisian pilgrims, i.e. the inhabitants of the coastal areas between Denmark and today's Belgian Flanders, who were on their pilgrimage to Rome.

[37] In the Migliorati palace, Ludovico, on the orders of his uncle, slaughtered the representatives of the Commune of Rome who had come to the pope to ask for guarantees for republican freedom.

[37] In 1600, this group of houses was demolished to erect the palace of the Commendatore dell'Ospedale, built by order of Gregory XIII (r. 1572–1585) by Nanni di Baccio Bigio.

[35] In addition, besides rebuilding the Hospital of Santo Spirito, on the first of January 1474 he issued a papal bull granting many benefits to those who built houses in the Borgo that were at least 7 canne (15 m (49 ft) ca.)

[39] At the turn of the 15th and 16th centuries, Palazzo della Rovere was built on the northern side of the street, but its main façade faced Piazza Scossacavalli and Borgo Vecchio.

[42] In 1544 Pope Paul III (r. 1534–1549) had Antonio da Sangallo the Younger elevate and complete the church of Santo Spirito, apart from the façade, which was built under Sixtus V (r. 1585–1590) by Ottavio Mascherino.

The Oratory of the Nunziatina was demolished and rebuilt in a different context along the Lungotevere Vaticano with a modern framework built according to the laws of structural engineering .

[53][54] Several minor buildings were demolished to allow the reconstruction of Palazzo Alicorni, located between Borgo S. Spirito and St. Peter's Square and destroyed in 1930, while other late-Renaissance houses after the junction with Via dei Penitenzieri were demolished for the construction of the Curia Generalizia dei Gesuiti (the headquarter of the Jesuite order), located on the slopes of the Palazzolo hill.

[56][57] The church of San Lorenzo in Piscibus, whose apse faced the street, was brought back to its medieval state and incorporated into the southern propylaeum of Piazza Pio XII.