A major highlight of the Duomo's interior is the flooring , which features a mosaic of 59 etched and inlaid marble panels painstakingly created from 1372 to 1547. Some of the top artists working in Siena lent their talents, including Domenico di Bartolo, Matteo di Giovanni, Pinturicchio, and especially Beccafumi, who designed 35 scenes (1517-47).
The mosaic panels in the nave and aisles are usually uncovered, but the most precious ones under the apse and in the transepts are protected by cardboard flooring and uncovered only from August 23 to October 3 each year in honor of the Palio. The floor is traversed by penitents on their knees.
The floor panel visible in the Duomo's center, in the left transept, is Matteo di Giovanni's fantastic 1481 Massacre of the Innocents (a theme with which the painter was obsessed - see also his disturbing paintings of it in the Palazzo Pubblico and Santa Maria dei Servi).
Another interior highlight is the famous Gothic octagonal pulpit by Nicola Pisano (1266–1268), assisted by his son Giovanni. The elegantly Gothic panels depict the life of Christ in crowded, detailed turmoil, divided by figures in flowing robes. The columns are supported on the backs of lions with their prey and cubs, and the base of the central column is a seated congregation of philosophers and figures representing the liberal arts.
The north transept has a bronze statue by Donatello of an emaciated St. John the Baptist, a companion piece to his Mary Magdalene in Florence. The Renaissance high altar is flanked by candelabra-carrying angels by Beccafumi.
About halfway down the nave and on the left is the entrance to the Libreria Piccolomini, a library commissioned by Francesco Piccolomini (Pope Pius III) to house the books of his uncle Aeneas (Pius II). The impressive life of Aeneas/Pius II is celebrated in a series of brilliantly colorful frescoes by Pinturicchio, from his attendance at the Council of Basel as a secretary, though his crowning as poet laureate by the Holy Roman Emperor, to, in the second-to-last panel, his canonization of St. Catherine of Siena.
Beneath the Duomo in the baptistery is bas-reliefs by Donatello, Ghiberti, Jacopo della Quercia and other 15th-century sculptors. The Museum of the Opera del Duomo contains Duccio's famous Madonna (1308–1311).
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