Thessaloniki was, for much of the existence of the Byzantine Empire, its second largest city. Evidence of this history can still be seen in the 15 Paleochristian and Byzantine Monuments of Thessaloniki that are included in the UNESCO World Heritage List. Thessaloniki was a multicultural city that a prosperous yet tumultuous history from the Roman era to the Ottoman era.
The city was founded in 315 BC on the site of an earlier settlement by Cassander, who gave it the name of his wife, the sister of Alexander the Great. After the military conquest of Macedonia by the Romans (146 BC), Thessaloniki began to play an increasingly important role, acting as a highly important transit center in the elaborate road network created by the Romans in the Balkan Peninsula. It gained prominence starting at the end of the 3rd century due to its strategic location with regard to both barbarian invasions across the Danube and East-West confrontation.
During the Tetrarchy, Galerius established Thessaloniki as his seat, making it one of the capitals of the Roman Empire. His residence in Thessaloniki was accompanied by burgeoning building activity (including the Palace of Galerius, the Arch of Galerius, the Rotunda and the Hippodrome). It was at this date that Thessaloniki acquired its definitive form as a walled city, which it retained down to the end of the 19th century. 
During his war against Licinius, Thessaloniki was briefly the headquarters of Constantine. From the mid-5th century, Thessaloniki was the capital of the prefecture of Illyricum and an important episcopal center, created according to tradition by St. Paul. The bishopric was at first under the jurisdiction of Rome, but from the second half of the 6th century Constantinople strengthened its grip on Thessaloniki, and around 733 the archbishopric was transferred to the jurisdiction of the patriarchate of Constantinople. In the 7th-9th centuries, Thessaloniki was administered by an eparch, later by a doux. 
In 390 Emperor Theodosius I massacred thousands of citizens in the Hippodrome of Thessaloniki as punishment for the murder of one of his barbarian generals. The Germanic invasions of the 4th and 5th centuries bypassed Thessaloniki; in the 6th century, however, Procopius spoke of the city as "easily assailable by barbarians." In 479, when the news of an imminent Ostrogothic attack spread in Thessaloniki, the inhabitants expressed no confidence in the eparch and took the keys to the gate away from him, entrusting them to the bishop. More dangerous were the Slavic sieges of Thessaloniki from the end of the 6th century onward, repelled according to contemporary legend only by the supernatural intervention of St. Demetrius. While Thessaloniki remained in Byzantine hands, most of its hinterland was overwhelmed by Slavic settlers. 
These sieges failed to interrupt the cultural evolution of the city, however, which reached a very high level at the time of the Palaiologoi. The conversion of the Slavs by Cyril and Methodius, two brothers from Thessaloniki, in the 9th century, and the creation of an alphabet in which the Slav language could be written, marked the beginning of the cultural influence exercised by Thessaloniki on the Slav world, which reached its culmination in the 14th century. It was mainly through Thessaloniki that the ideology and cultural influence of Byzantium was channeled to the Balkans. 
The Bulgar invasion under Simeon I of Macedonia did not affect Thessaloniki, but Leo of Tripoli captured and sacked the city in 904. The peace with Bulgaria and its subsequent conquest by Basil II transformed Thessaloniki into the major center of economic and cultural interchange in the southern Balkans. It seems that Thessaloniki became an important trade center in the 12th century, attracted merchants from the Steppes to the Mediterranean. Italian merchants began to organize colonies there, and in 1185 the Normans temporarily occupied the city. After the Fourth Crusade, Boniface of Montferrat became king of Thessaloniki, with territory in Macedonia and western Thrace and interests as distant as the Peloponnesus. After the Battle of Adrianople in 1205 Kaloyan besieged Thessaloniki, but the city withstood the attack.
In 1224, Theodore Komnenos Doukas  of Epirus captured Thessaloniki and it remained part of the Despotate of Epirus until it fell to John III Vatatzes in 1246. In the spring of 1308 the Catalan Grand Company unsuccessfully besieged Thessaloniki, and beginning in 132o the city was a focus of contention between Andronikos II and Andronikos III. In 1334 the walls of Thessaloniki stopped the advance of Stefan Uroš IV Dušan, but the Serbs attacked again in 1341. In the 1340s Thessaloniki fell temporarily under the control of the Zealots. The Ottomans attacked Thessaloniki in autumn 1383 and the city fell in April 1387. It returned briefly to Byzantine hands but was taken by Bayezid I in 1394.
In the aftermath of the battle of Ankara in 1402 Byzantines regained Thessaloniki and a despotate was established there. In 1423, however, the Despot Andronikos surrendered the city to Venice, which agreed to respect the rights and privileges of the inhabitants. Murad II took the city in 1430 after a brief siege. 
The monuments surviving from over one thousand years of history of the Byzantine city are representative of Byzantine culture and art over the centuries. These can particularly be seen in the Byzantine churches of Thessaloniki, which also contain remarkable mosaics and frescoes from Late Antiquity to the Late Byzantine Era. Immediately after the capture of Thessaloniki by the Turks in 1430, the Byzantine city quickly acquired the personality of an Islamic center of the Ottoman Empire through the construction of large public and religious buildings. Thessaloniki had a multiracial character, however, which became even more pronounced after 1492, when a large number of Jews settled in the city.