In 282 BC, Philetaerus deserted Lysimachus, offering himself and the important fortress of Pergamon, along with its treasury, to Seleucus I Nicator, who defeated and killed Lysimachus at the Battle of Corupedium in 281 BC. Seleucus was killed a few months later.

Philetaerus, especially after the death of Seleucus, enjoyed considerable autonomy despite being nominally under the Seleucids. He acquired considerable wealth because Pergamon had been the treasure-hold of Lysimachus and extended his power and influence beyond Pergamon. He contributed troops, money, and food to the city of Cyzicus, in Mysia, for its defense against the invading Gauls, thus gaining prestige and goodwill for him and his family.

Philetaerus' nephew and adopted son Eumenes I succeeded him upon his death in 263 BC.

Eumenes I rebelled and defeated the Seleucid king Antiochus I Soter near the Lydian capital of Sardis in 261 BC.

Pausanias wrote that the greatest achievement of Attalus I (r. 241–197 BC) was his defeat of the Gauls, by which he meant the Galatians, Celts who had migrated to central Asia Minor and established themselves as a major military power.

Attalus defeated the Gauls and Antiochus in the battle of Aphrodisium and in a second battle in the east.

Attalus I then fought Antiochus alone in a battle near Sardis and in the Battle of the Harpasus in Caria in 229 BC.

In 223 BC, Seleucus III crossed the Taurus but was assassinated. Achaeus assumed control of the army.

Achaeus assumed control of the army. Antiochus III the Great then made him governor of Seleucid territories north of the Taurus. Within two years he recovered the lost territories and forced Attalus within the walls of Pergamon. However, he was accused of intending to revolt, and to protect himself he proclaimed himself king.

In 218 BC, Attalus recaptured his former territories with the help of some Thracian Gauls.

Achaeus returned from his victorious campaign in 217 BC and hostilities between the two resumed.

Attalus made an alliance with Antiochus III, who besieged Achaeus in Sardis in 214 BC.

The Attalids became allies of Rome during the First Macedonian War (214–205 BC) and supported Rome in subsequent wars.

Attalus I, who had helped the Romans in the first war, also provided them with assistance in the Second Macedonian War (200–197 BC).

Before he became king, Attalus II was a military commander. In 190 BC he took part in the Battle of Magnesia, which was the final victory of the Romans in the war against the Seleucids.

Eumenes II (r. 197–159 BC) supported Rome in the Roman–Seleucid War (192–188 BC).

In 188 BC, after the war against the Seleucids, the Romans seized the possessions of the defeated Antiochus III the Great in Asia Minor and gave Mysia, Lydia, Phrygia, and Pamphylia to the kingdom of Pergamon and Caria Lycia and Pisidia, in the southwestern corner of Asia Minor, to Rhodes, another Roman ally. Later the Romans gave these possessions of Rhodes to Pergamon.

In 149 BC, Attalus helped Nicomedes II Epiphanes to seize the Bithynian throne from his father Prusias II.

The last Attalid king, Attalus III died and bequeathed the kingdom to the Roman Republic in 133 BC.

The Romans were reluctant to take on territory in Asia Minor and did not take charge of the kingdom. Aristonicus claimed to be the illegitimate son of Eumenes II, assumed the dynastic name of Eumenes III, claimed the throne, instigated a rebellion, and in 132 BC "occupied Asia, which had been bequested to the Roman people and was supposed to be free".

In 131 BC Rome sent an army against him which was defeated. The Romans defeated Eumemes III in 129 BC. They annexed the former kingdom of Pergamon, which became the Roman province of Asia.