Construction on the cathedral began in 1063 (1064 according to the Pisan calendar of the time) by the architect Buscheto, and expenses were paid using the spoils received fighting against the Muslims in Sicily in 1063.

In the same year, St. Mark's Basilica began its reconstruction in Venice, evidence of a strong rivalry between the two maritime republics to see which could create the most beautiful and luxurious place of worship.

[citation needed] The chosen area had already been used in the Lombard era as a necropolis and at the beginning of the 11th century a church had been erected here, but never finished, that was to be named Santa Maria.

The first radical interventions occurred after the fire of 1595, following which the roof was replaced and sculptors from the workshop of Giambologna, among whom were Gasparo Mola and Pietro Tacca, created the three bronze doors of the facade.

In the early 18th century began the redecoration of the inside walls of the cathedral with large paintings, the "quadroni", depicting stories of the blesseds and saints of Pisa.

Successive interventions occurred in the 19th century and included both internal and external modifications; among the latter was the removal of the original facade statues (presently in the cathedral museum) and their replacement with copies.

The inside offers a spatial effect similar to that of the great mosques thanks to the use of raised lancet arches, the alternating layers of black and white marble, and the elliptical dome, inspired by the Moors.

The griffin was placed on a platform atop a column rising from the gable above the apse at the east end of the roof, probably as continuation of the original construction that started in 1064.

The heavy bronze doors of the façade were newly designed, executed and completed in 1602 by sculptors from the circle of Giambologna on the expense of Ferdinando I de' Medici, the Grand Duke of Tuscany.

Contrary to what might be thought, from the beginning the faithful entered the cathedral through the Gate of Saint Rainerius, found in the south transept of the same name, which faces the bell tower.

It has a wooden 17th-century coffered ceiling, painted and decorated with gold leaf, made by Domenico and Bartolomeo Atticciati; it bears the Medici coat of arms.

The inside of the dome, found where the central nave and the transepts cross, is decorated using a rare painting technique called encaustic[7][8] and depicts the Virgin in glory with saints by the Pisan artists Orazio and Girolamo Riminaldi (1627–1631).

[9] The granite Corinthian columns between the nave and the apse come from the mosque of Palermo, and are Pisan spoils retained in 1063 after a successful joint attack with the Normans on the Muslims in that city.

With its intricate architecture and its complex sculptural decoration the work presents one of the most sweeping narratives of the 13th-century imagination and reflects the religious renewal and fervor of the era.

The tomb, sculpted by Tino da Camaino between 1313 and 1315, was also dismantled then reconstructed and today sits in the right transept, while its original position was in the center of the apse as a sign of the city's ghibbeline adherence.

In the Baroque style are: the Disputation of the Holy Sacrament by the Sienese painter Francesco Vanni, and the Cross with Saints by Genoan Giovanni Battista Paggi.

During the Middle Ages, these panels were reused for burials of nobles (among them Beatrice of Lorraine) and other well known persons, such as the architect Buscheto himself, who is buried under the outer left arch of the west facade.