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Seriphos was once ruled by king Polydektes, brother of the fisherman Diktys, in Greek mythology. Once Diktys had saved Danae and Perseus, the daughter and grandson of the Argive King Akrisios, from the sea, Polydektes wanted to marry Danae. Perseus opposed this, and was tasked by Polydektes to slay the gorgon Medusa and come back with her head. Perseus did as asked, and when he returned, the sight of the gorgon's head turned Polydektes into stone.
During the Peloponnesian War, the island was home to Theras, a friend of the Athenian sculptor Phidias. In 431 BCE, after being pursued by the Cult of Kosmos, Phidias sent a letter to Theras, instructing him to meet him at the Chora as he planned his escape from Athens through the Port of Piraeus. Theras later met him and the Spartan misthios Kassandra, the latter escorting him aboard the Adrestia. Theras thanked Kassandra and provided her a note which he had intercepted, written by Brison, Phidias' to-be assassin.
Sometime later, several Cult of Kosmos guards travelled to Seriphos, interrogating Theras about a series of symbols that he and Phidias had been investigating. Theras was later rescued by Kassandra, whom he gave a map to detailing the location of the symbol.