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In September 1259, William of Villehardouin was defeated and captured, along with many of his nobles, at the Battle of Pelagonia, by the forces of the Nicaean emperorMichael VIII Palaiologos. Two years later, the Nicaeans recaptured Constantinople, putting an end to the Latin Empire and restoring the Byzantine Empire. At this point, the emperor concluded an agreement with the captive prince: William and his men would be set free in exchange for an oath of fealty, and for the cession of Monemvasia, Grand Magne, and Mystras. The handover was effected in 1262, and henceforth Mystras was the seat of the governor of the Byzantine territories in the Morea. Initially this governor (kephale) was changed every year, but after 1308 they started being appointed for longer terms. Almost immediately on his return to the Morea, William of Villehardouin renounced his oath to the emperor, and warfare broke out between Byzantines and Franks. The first Byzantine attempts to subdue the Principality of Achaea were beaten back in the battles of Prinitsa and Makryplagi, but the Byzantines were firmly ensconced in Laconia. Warfare became endemic, and the Byzantines slowly pushed the Franks back. The insecurity engendered by the raids and counter-raids caused the inhabitants of Lacedaemon to abandon their exposed city and settle at Mystras, in a new town built under the shadow of the fortress.
From 1348 until its surrender to the Ottoman Turks on 31 May 1460, Mystras was the residence of a Despot who ruled over the Byzantine Morea, known as the "Despotate of the Morea". This was the city's golden age; according to the Oxford Dictionary of Byzantium, Mystras "witnessed a remarkable cultural renaissance, including the teaching of Plethon [..], and attracted artists and architects of the highest quality".
The frescos in the Peribleptos Monastery Church, dating between 1348 and 1380, are a very rare surviving late Byzantine cycle, crucial for the understanding of Byzantine art.
Mystras is situated on the slopes of Taygetos Mountain. The archaeological site stands above the modern village of Mystras and the city of Sparta. The greenery surrounding the area is composed mainly by pine trees and cypresses. Some small rivers and lakes are found in the region. 
Romer, John (1997), Byzantium: The Lost Empire; ABTV/Ibis Films/The Learning Channel; 4 episodes; 209 minutes. (In Episode 4 ["Forever and Ever"], presenter Romer devotes a section to strolling through Mistra evoking its glory in the days of Plethon.)