The Venetian cartographer Vincenzo Coronelli reports that Spinalonga was not always an island, but was once linked with the adjacent peninsula of Kolokitha. He mentions that in 1526, the Venetians cut down a portion of the peninsula and thus created the island. Because of its position the island was fortified from its earliest years in order to protect the entranceway of the port of Ancient Olous.

In 1578 the Venetians charged the engineer Genese Bressani to plan the island's fortifications. He created blockhouses at the highest points of the northern and southern side of the island, as well as a fortification ring along the coast of the island that closed out any hostile disembarkation. In 1579, the General Previsor of Crete Luca Michiel put the foundation stone of the fortifications. In 1584, the Venetians, realizing that the coastal fortifications were easy to conquer by the enemies attacking from the vicinal hills, decided to strengthen their defense by constructing new fortifications at the top of the hill. The Venetian fire would thus have bigger throw, rendering Spinalonga an impregnable sea fortress, one of the most important in the Mediterranean basin. The Venetians kept control of the island until the Ottoman Empire took possession of it in 1715.

The island was used as a leper colony, from 1903 to 1957. It is notable for being one of the last active leper colonies in Europe.

Today, the unoccupied island is one of the main tourist attractions in Crete. In addition to the abandoned leper colony and the fortress, Spinalonga is known for its small pebble beaches.

The small island's fame rose recently, following the success of the bestselling book "The Island" by Victoria Hislop, which is set in Spinalonga and shares the fictional story of a family's ties to the leper colony.

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