The Frankish kingdom of Thessalonike was established within the Macedonian region by Boniface of Monferrat after the capture of Constantinople by the Crusaders (1204). In 1224 Theodore Doukas, ruler of the despotate of Epirus, overran the Frankish kingdom of Thessalonike and incorporated its territory into his state.
His coronation as "king and emperor of the Romans" provoked a quarrel with the empire of Nicaea. Clashes between the two states over control of Macedonia were long lasting and ended only with the recapture of Constantinople in 1261 by the forces of Nicaea and the subjection of Macedonia and Thrace to the reconstructed, but territorially extremely reduced, Byzantine Empire.
Macedonia and Thrace were severely devastated by violent conflicts generated by civil wars (1321-1354), while Ottoman advances at the end of the 14th century restricted Byzantine sovereignty to merely small parts of them. Thessalonike was first taken by the Turks in 1387 after a four-year siege, but was handed back to the Byzantines in 1403.
In 1423 Andronikos, governor of Thessalonike, ceded the city to the Venetians because he was unable to protect it effectively against a new Turkish threat. Despite Venetian efforts to defend it, Sultan Murad II, leading the Turkish army himself, captured Thessalonike in 1430.