This canal is the main water road in Venice, crossing the city from its north-westernly corner up to the south-easternly one. It begins near Piazzale Roma (Rome's Square), the entrance point to the city from mainland where is the end of line for land transportation, and leads to Piazza San Marco and to the lagoon, in front of the isle of Giudecca.

On both sides of the canal, crossed by boats since the Middle Ages, there were once many watermills powered by tides, the wool and silk factories, the old dockyards of the Republic. By the gradual transformation of this area in residencial zone, on its sides had been built the palaces of the most important noble families in Venice, which nowadays hosts museums, institutions or luxury hotels.

The most representative palaces on the Grand Canal are: Bridge and Church of the Scalzi (Barefoot), in baroque style; Palace Labia, from XVIII century; Palace Vendramin Calergi, syntesis of Byzantyn and Gothic architecture, now seat of the Municipal Casiṇ; Ca' d'Oro (Golden House), so called by the splendid golden decorations, now restored and seat of Franchetti Gallery; Ca da Mosto, where was the most renowned hotel in the city during XVI and XVIII century; Fondaco dei Tedeschi (Germans' Storehouse), seat of Germanic merchants built in XIII century: it had frescoes by Giorgione and Tiziano, nowadays seat of the main Post Office in Venice; Palace Mocenigo, complex of four noble palaces; Palace Grassi, built in XVIII century, which hosts some very important exhibitions; Fondaco dei Turchi (Turks' Storehouse), restored during XIX century, hosts the Museum of Natural History; Ca' Pesaro, by Longhena, today hosts the Museum of Oriental Art and the Gallery of Modern Art; Ca' Foscari, by the powerful family of Foscari, now seat of the University of Venice; Ca' Rezzonico, a project by Baldassarre Longhena, where is the Museum of Venetian Settecento, with paintings by Tiepolo, Canaletto, Longhi, Guardi; Palace Moro, which inspired Shakespeare for the scenery of Otello; Palace Venier dei Leoni, which hosts the collection by Peggy Guggenheim.