The Piazza was the focal point of the city, and served as a center of worship due to its proximity to the Basilica and the government (through the Palazzo Ducale). The Piazza opened out onto the Venetian Lagoon, and as such, was the site of a travel booth.
Due to its large size and proximity to many important buildings, the Piazza was a common place to hold meetings. As such, the Venetian conspirators met in the square to discuss their plans to assassinate Doge Giovanni Mocenigo.
Ezio Auditore da Firenze rendezvoused with Antonio de Magianis in the Piazza, in order to scout out a means to enter the well-guarded Palazzo Ducale, though they would find none short of flying in. This inspired Ezio to use a flying machine built by his friend Leonardo da Vinci to gain access; the plan worked to an extent, though Ezio arrived too late to save the Doge, while the machine itself crashed in the square after knocking a guard off the roof, having been shot by a flaming arrow.