This system of sestieri originated in Roman times, when it corresponded with the organization of military camps, which were divided into four parts (quarters).

A sestiere (plural: sestieri) is a subdivision, quarter or neighborhood used in certain Italian towns and cities. The word is from sesto, or sixth; and is thus used only for towns divided into six districts. Venice is the best example of this subdivision, with its six sestieri: Cannaregio, San Polo, Dorsoduro (including the Giudecca and Isola Sacca Fisola), Santa Croce, San Marco (including San Giorgio Maggiore) and Castello (including San Pietro di Castello and Sant'Elena). Historically, each sestiere was administered by a procurator and his staff.

The sestieri of today were formed in approximately the twelfth century. In 1171, the Byzantine emperor Manuele II had arrested all Venetians in Constantinople and sequestered their wealth, forcing the Venetian Republic to instate a new tax in order to finance the war they were fighting against the Byzantines. The city was then divided into these "sestieri" with the aim to recruit soldiers and sailors for a punitive expedition against the Byzantine Empire. This division then remained and served other administrative functions.

Still today every sestiere has its own civic numbering system, with the exception of the islands not connected by a bridge. Due to the complexity of the streets and viability of Venice, very often the house numbers are different – and very confusing- within a close distance to one another.