It is especially known for the Treaty of Cave, signed on September 12, 1557 by plenipotentiaries of Pope Paul IV and Fernando Álvarez de Toledo, the Spanish viceroy of Naples.
He also appears as a character in John Webster's Jacobean revenge drama The White Devil (1612).
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He has been Venetian resident ambassador at the courts of emperor Charles V (1543-46), Suleiman the Magnificent (1550-52) and pope Paul IV (1555-58), and member of the Council of Ten (1552).
Under Dona Gracia, the House of Mendes dealt with King Henry II of France, Holy Roman Emperor Charles V, his sister Mary, Governess of the Low Countries, Popes Paul III and Paul IV, and Sultan Suleiman the Magnificent, Sultan of the Ottoman Empire.
In 1547 it was again occupied by the Duke of Alba in a war against Pope Paul IV, and in 1744 by the Austrians.