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The church is thought to have originally been constructed in the 9th century to house the relics of Saint Zaccaria, the father of John the Baptist. Although the original structure burnt down in 1105 a crypt still exists which holds the remains of 8 former doges (dukes of Venice). In the 12th century the church was rebuilt and again in the 14th century, this time in the Gothic architectural style. Antonio Gambello and Mauro Codussi designed the church we see today which was completed in 1515.

The structure has a Byzantine campanile and a Gothic style choir but apart from that it is predominantly Renaissance is design. The façade appears to rise 6 levels from the ground, and is topped by a semi-circular roof and rounded corners. The incredible art displayed on the church walls between large Gothic windows includes work by Giovanni Domenico Tiepolo, Palma the Elder, Antonio Balestra, Giovanni Bellini, Giuseppe Salviati, Titoretto, Angelo Trevisani and Van Dyck. The highlight of this church's art work is Bellini's painting of Madonna with Child created in 1505.

In the 18th century the adjacent Benedictine convent gained infamy as it took in unruly daughters from rich and influential families. These girls then got up to fun and games with a string of young, handsome "pilgrims".