Pope Julius' scheme for the grandest building in Christendom was the subject of a competition for which a number of entries remain intact in the Uffizi Gallery, Florence. It was the design of Donato Bramante that was selected, and for which the foundation stone was laid in 1506. This plan was in the form of an enormous Greek Cross with a dome inspired by that of the huge circular Roman temple, the Pantheon. The main difference between Bramante's design and that of the Pantheon is that where the dome of the Pantheon is supported by a continuous wall, that of the new basilica was to be supported only on four large piers. This feature was maintained in the ultimate design. Bramante's dome was to be surmounted by a lantern with its own small dome but otherwise very similar in form to the Early Renaissance lantern of Florence Cathedral designed for Brunelleschi's dome byMichelozzo.

Bramante had envisioned that the central dome be surrounded by four lower domes at the diagonal axes. The equal chancel, nave and transept arms were each to be of two bays ending in an apse. At each corner of the building was to stand a tower, so that the overall plan was square, with the apses projecting at the cardinal points. Each apse had two large radial buttresses, which squared off its semi-circular shape.

When Pope Julius died in 1513, Bramante was replaced with Giuliano da Sangallo, Fra Giocondo and Raphael. Sangallo and Fra Giocondo both died in 1515, Bramante himself having died the previous year. The main change in Raphael's plan is the nave of five bays, with a row of complex apsidal chapels off the aisles on either side. Raphael's plan for the chancel and transepts made the squareness of the exterior walls more definite by reducing the size of the towers, and the semi-circular apses more clearly defined by encircling each with an ambulatory.

In 1520 Raphael also died, aged 37, and his successor Baldassare Peruzzi maintained changes that Raphael had proposed to the internal arrangement of the three main apses, but otherwise reverted to the Greek Cross plan and other features of Bramante. This plan did not go ahead because of various difficulties of both church and state. In 1527 Rome was sacked and plundered by Emperor Charles V. Peruzzi died in 1536 without his plan being realized.

At this point Antonio da Sangallo the Younger submitted a plan which combines features of Peruzzi, Raphael and Bramante in its design and extends the building into a short nave with a wide façade and portico of dynamic projection. His proposal for the dome was much more elaborate of both structure and decoration than that of Bramante and included ribs on the exterior. Like Bramante, Sangallo proposed that the dome be surmounted by a lantern which he redesigned to a larger and much more elaborate form. Sangallo's main practical contribution was to strengthen Bramante's piers which had begun to crack.

On 1 January 1547 in the reign of Pope Paul III, Michelangelo, then in his seventies, succeeded Sangallo the Younger as "Capomaestro", the superintendent of the building program at St Peter's. He is to be regarded as the principal designer of a large part of the building as it stands today, and as bringing the construction to a point where it could be carried through. He did not take on the job with pleasure; it was forced upon him by Pope Paul, frustrated at the death of his chosen candidate, Giulio Romano and the refusal of Jacopo Sansovino to leave Venice. Michelangelo wrote "I undertake this only for the love of God and in honour of the Apostle." He insisted that he should be given a free hand to achieve the ultimate aim by whatever means he saw fit.

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