Mithridates entertained ambitions of making his state the dominant power in the Black Sea and Anatolia. He first subjugated Colchis, a region east of the Black Sea, and prior to 164 BC, an independent kingdom. He then clashed for supremacy on the Pontic steppe with the Scythian King Palacus. The most important centres of Crimea, Tauric Chersonesus and the Bosporan Kingdom readily surrendered their independence in return for Mithridates' promises to protect them against the Scythians, their ancient enemies. After several abortive attempts to invade the Crimea, the Scythians and the allied Rhoxolanoi suffered heavy losses at the hands of the Pontic general Diophantus and accepted Mithridates as their overlord.

The young king then turned his attention to Anatolia, where Roman power was on the rise. He contrived to partition Paphlagonia and Galatia with King Nicomedes III of Bithynia. It was probably on the occasion of the Paphlagonian invasion of 108 BC that Mithridates adopted the Bithynian era for use on his coins in honour of the alliance. This calendar era began with the first Bithynian king Zipoites I in 297 BC. It was certainly in use in Pontus by 96 BC at the latest.

Yet it soon became clear to Mithridates that Nicomedes was steering his country into an anti-Pontic alliance with the expanding Roman Republic. When Mithridates fell out with Nicomedes over control of Cappadocia, and defeated him in a series of battles, the latter was constrained to openly enlist the assistance of Rome. The Romans twice interfered in the conflict on behalf of Nicomedes (95–92 BC), leaving Mithridates, should he wish to continue the expansion of his kingdom, with little choice other than to engage in a future Roman-Pontic war. By this time Mithradates had resolved to expel the Romans from Asia.

The next ruler of Bithynia, Nicomedes IV of Bithynia, was a figurehead manipulated by the Romans. Mithridates plotted to overthrow him, but his attempts failed and Nicomedes IV, instigated by his Roman advisors, declared war on Pontus. Rome itself was involved in the Social War, a civil war with its Italian allies. Thus, in all of Roman Asia Province there were only two legions present in Macedonia. These legions combined with Nicomedes IV's army to invade Mithridates' kingdom of Pontus in 89 BC. Mithridates won a decisive victory, scattering the Roman-led forces. His victorious forces were welcomed throughout Anatolia. The following year, 88 BC, Mithridates orchestrated a massacre of Roman and Italian settlers remaining in several Anatolian cities, essentially wiping out the Roman presence in the region. 80,000 people are said to have perished in this massacre. The episode is known as the Asiatic Vespers.

The Kingdom of Pontus comprised a mixed population in its Ionian Greek and Anatolian cities. The royal family moved the capital from Amasya to the Greek city of Sinope. Its rulers tried to fully assimilate the potential of their subjects by showing a Greek face to the Greek world and an Iranian/Anatolian face to the Eastern world. Whenever the gap between the rulers and their Anatolian subjects became greater, they would put emphasis on their Persian origins. In this manner, the royal propaganda claimed heritage both from Persian and Greek rulers, including Cyrus the Great, Darius I of Persia, Alexander the Great and Seleucus I Nicator. Mithridates too posed as the champion of Hellenism, but this was mainly to further his political ambitions; it is no proof that he felt a mission to promote its extension within his domains. Whatever his true intentions, the Greek cities (including Athens) defected to the side of Mithridates and welcomed his armies in mainland Greece, while his fleet besieged the Romans at Rhodes. Neighboring King of Armenia Tigranes the Great established an alliance with Mithridates and married one of Mithridates’ daughters, Cleopatra of Pontus. They would support each other in the coming conflict with Rome.

The Romans responded by organising a large invasion force to defeat him and remove him from power. The First Mithridatic War, fought between 88 BC and 84 BC, saw Lucius Cornelius Sulla force Mithridates VI out of Greece proper. After victory in several battles, Sulla received news of trouble back in Rome posed by his enemy Gaius Marius and hurriedly concluded peace talks with Mithridates. As Sulla returned to Italy Lucius Licinius Murena was left in charge of Roman forces in Anatolia. The lenient peace treaty, which was never ratified by the Senate, allowed Mithridates VI to restore his forces. Murena attacked Mithridates in 83 BC, provoking the Second Mithridatic War from 83 BC to 81 BC. Mithridates defeated Murena's two green legions at the Battle of Halys in 82 BC before peace was again declared by treaty.

When Rome attempted to annex Bithynia (bequested to Rome by its last king) nearly a decade later, Mithridates VI attacked with an even larger army, leading to the Third Mithridatic War from 73 BC to 63 BC. Lucullus was sent against Mithridates and the Romans routed the Pontic forces at the Battle of Cabira in 72 BC, driving Mithridates to exile into King Tigranes' Armenia. While Lucullus was preoccupied fighting the Armenians, Mithridates surged back to retake his kingdom of Pontus by crushing four Roman legions under Valerius Triarius and killing 7,000 Roman soldiers at the Battle of Zela in 67 BC. He was routed by Pompey's legions at the Battle of the Lycus in 66 BC. After this defeat, Mithridates VI fled with a small army to Colchis (modern Georgia) and then over the Caucasus Mountains to Crimea and made plans to raise yet another army to take on the Romans. His eldest living son, Machares, viceroy of Cimmerian Bosporus, was unwilling to aid his father. Mithridates had Machares killed, and Mithridates took the throne of the Bosporan Kingdom. Mithridates then ordered conscription and preparations for war. In 63 BC, Pharnaces II of Pontus, one of his sons, led a rebellion against his father, joined by Roman exiles in the core of Mithridates' Pontic army. Mithridates withdrew to the citadel in Panticapaeum, where he committed suicide. Pompey buried Mithridates in the rock-cut tombs of his ancestors in Amasya, the old capital of Pontus.

The death of Mithridates and his doughters..

Mithridates VI of Pontus allegedly attempted suicide by poison, this failed however because of his immunity to the poison, so he requested his Gaulish bodyguard and friend, Bituitus, to kill him by the sword. Mithridates VI or Mithradates VI,135-63 BC, aka Mithradates the Great or Eupator Dionysius. King of Pontus and Armenia Minor. From Hutchinson's History of the Nations, published 1915.