The 330 m high castle hill above today's Bergama has been inhabited since the 6th century BC, but it was not until the Hellenistic era that Pergamon blossomed into an ancient cosmopolitan city.

Based on finds of fragments of western Eastern Greek and Corinthian imported pottery from the late 8th century BC, a settlement can already be proven in Archaic times. Pergamon was first mentioned in literature in 400/399 BC.
Traces of pre-Hellenistic settlement in the 4th century B.C. are rare, as the site was repeatedly radically redesigned in subsequent periods and older buildings were mostly completely demolished in the course of large terraces.
The temple of Athena can be traced back to the 4th century BC, but altar foundations and walls of the 4th century BC can also be found in the Demeter sanctuary.

Alexander the Great liberated this area and Pergamon of Persian domination with him. At the time of the Diadochi Pergamon belonged like the rest of Mysia to the dominion of the Lysimachos. He used Philetairos to guard the castle, where 9,000 talents and a large part of the Lysimachos' spoils were deposited. With this treasure, Philetairos succeeded in becoming independent after the death of Lysimacho in 281 BC and founded his own dynasty with the Attalids.

The Attalids ruled Pergamon from 281 to 133 B.C. The city became the centre of the Pergaman Empire. Eumenes I. did not yet accept the royal title. Only his successor Attalos I did this. Now there was a Pergamian Empire independent from all sides, which reached the peak of its power and expansion in 188 BC.

Pergamon flourished under the brothers Eumenes II and Attalos II, which was reflected in the monumental development of the city. The aim was to create a second Athens, an Athens of artistic and cultural activity, as it prevailed in Pericles' time and dominated large parts of Greek artistic creation.
The two brothers were the most distinctive witnesses of an Attalid trait that was rare in this form among the Hellenistic dynasties: a marked sense of family that knew neither competition nor intrigue. Eumenes II and his brother Attalos II, who bore the nickname Philadelphos, the brother-lover, were even regarded as embodiments of the legendary brother couple Kleobis and Biton.

Attalos III of Pergamum, who died 133 B.C. without descendants, bequeathed Pergamum to the Romans. In 129 B.C., the Roman province of Asia emerged from the kingdom of Pergamon, and the city itself was declared free.

Under Augustus, the first imperial cult was established in Pergamon in the province of Asia. Pliny the Elder was considered Pergamon's most important city and the local aristocracy continued to produce outstanding men.

Under Trajan and his successors, a comprehensive new and redesign followed, the construction of a Roman "new city" at the foot of the Acropolis, and Pergamon was the first city in the province to receive a second neo-corie from Trajan in 113/114 A.D. Hadrian elevated the city to the rank of a metropolis in 123 A.D., thereby distinguishing it from its competitors Ephesus and Smyrna.
In the middle of the 2nd century Pergamon was beside these two the biggest city of the province and had about 200 000 inhabitants. Caracalla gave the city a third neo-corie, but already the decline began.
Finally, the economic power of Pergamon dwindled among the soldier emperors, which lost its importance and was threatened by the invasions of the Goths.

In Byzantine times, a retreat of the settlement to the castle hill can be observed, which was protected by a 6-metre thick wall made of spolia.
Pergamon, the seat of one of the seven oldest main churches in Asia Minor, was founded in 716 by the Arabs under Maslama b. Abd-al-Malik conquered, large parts of the population destroyed. After the Arabs gave up their attempt to conquer Constantinople (717-718), the city was rebuilt and fortified.

Under Leo III Pergamon belonged to the theme Thrakesion, since Leo VI to the theme Samos. Although it suffered during the advance of the Seljuks to Western Anatolia after the Battle of Manzikert, it remained a prosperous city under the Byzantine Comnen dynasty.
Under Isaac Angelos, the town became an archbishopric, having previously been the suffragan bishopric of Ephesus.
After the conquest of Constantinople in 1204 in the fourth crusade, Pergamon became part of the empire of Nikaia.

When around 1250 the later emperor Theodoros II visited Laskaris Pergamon, he was shown the house of Galen, but he saw the amphitheatres of the city destroyed, and apart from the walls, to which he devoted some attention, only the vaults of the river Selinus were worth mentioning to him.
The splendid buildings of the Attalids and the Romans were at that time only plundered ruins. In 1345 Pergamon finally became part of the Ottoman Empire.

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