With the conquered territories firmly in Macedonian control, Alexander completed the final preparations for the invasion of Asia.  The 22 year-old king appointed Philip's experienced general Antipater as regent in his absence to preside over the affairs of Macedonia and Greece, left him a significant force of 13,500 Macedonian soldiers to watch Greece, Thrace, Illyria, and protect Macedonia, and set out for the Hellespont (modern Dardanelles) in the spring of 334 BC.

As his ship approached the Asia Minor's coast, he threw his spear from abroad and stuck it in the ground. He stepped onto the shore, pulled the weapon from the soil, and declared that the whole of Asia would be won by the Macedonian spear.   

In the army there were 25,000 Macedonians, 7,600 Greeks, and 7,000 Thracians and Illyrians, but the chief officers were all Macedonians, and Macedonians also commanded the foreign troops.  Alexander's second in command was Philip's general Parmenio, the other important commanders being Perdiccas,Craterus, Coenus, Meleager,Antigonus and Parmenio's son Philotas. The army soon encountered the forces of King Darius III. There were 40,000 Persians and Greeks (20,000 each) waiting for them at the crossing of the river Granicus, near the ancient city of Troy.  These Greeks had joined the Persians in the years following the defeat of the Greek army by Philip II at Chaeronea.  It is important to note the number of Greeks on the both sides. The Greeks in the Macedonian train were mobilized by the Macedonians, and historians Peter Green and Ulrich Wilken speak of them as hostages that would ensure the good behavior of their countrymen left behind in Greece under the watch of Antipater's Macedonian garrisons.  Not surprisingly, the Greeks in Alexander's army played insignificant role in the upcoming battles, only to be discharged when convenient. But far greater number of Greeks joined the Persians brushing away the memory of the Persian invasion of Greece some 150 years ago. The ancient Greek historian  Arrian cited the "old racial rivalry between the Greeks and Macedonians" that led to this hatred on both sides. 

The Macedonians defeated the Persians and put them to flight and although the Greeks held their ground and fiercely fought, the battle ended in Macedonian victory.  Almost the entire Greek force was annihilated. 18,000 Greeks perished on the banks of Granicus and the 2,000 survivors were sent to forced labor in Macedonia. The Macedonians lost only 120 men according to tradition.

Alexander then led the army south across Asia Minor.  Ironically, it is not the Persians but the Greek coastal cities which gave the greatest resistance to the Macedonians.  The Greek commander Memnon and his men considerably slow down the advance of Alexander and many Macedonians died during the long and difficult sieges of the Greek cities of Halicarnassus, Miletus, Mylasa.  But at the end the Macedonian army defeated the enemy and conquered the coast of Asia Minor. Alexander then turned northward to central Asia Minor, to the city of Gordium.

Gordium was a home of the famous so-called Gordian Knot. Alexander knew the legend that said that the man who could untie the ancient knot was destined to rule the entire world. To that date nobody had succeeded in raveling the knot. But the young Macedonian king simply slashed it with his sword and unraveling its ends. 

Darius's army greatly outnumbered the Macedonians, but the Battle of Issus ended in a big victory for Alexander. Ten's of thousands of Persians, Greeks, and other Asiatic soldiers were killed and king Darius fled in panic before the Macedonian phalanx, abandoning his mother, wife, and children behind.  Alexander treated them with the respect out of consideration for their royalty.

The victory at Issus opened the road for Syria and Phoenicia.  In early 332, Alexander sent general Parmenio to occupy the Syrian cities and himself marched down the Phoenician coast where he received the surrender of all major cities except the island city of Tyre which refused to grant him access to sacrifice at the temple of the native Phoenician god Melcart.  A very difficult seven-month siege of the city followed.  In an enormous effort, the Macedonians begun building a mole that would connect the island-city with the coast.  Tons of rocks and wood were poured into the water strip separating the island from the coast but its construction and the attacks from the city walls cost Alexander many of his bravest Macedonians.  Although seriously tempted to lift the siege and continue marching on Egypt, Alexander did not abandon the project and continued the siege, surrounding the island with ships and blasting the city walls with catapults.  When the walls finally gave in, the Macedonians poured their anger over the city defenders - 7,000 people were killed, 30,000 were sold as slaves.  Alexander entered the temple of Melcart, and had his sacrifice.  

During the seven-month siege of Tyre, Alexander received a letter from Darius offering a truce with a gift of several western provinces of the Persian Empire, but he refused to make peace unless he could have the whole empire.  He continued marching south toward Egypt but was again held up by resistance at Gaza.  The Macedonians put the city under a siege which lasted two months, after which the scenario of Tyre was repeated.  With the fall of Gaza, the whole Eastern Mediterranean coast was now secured and firmly in the hands of the Macedonians. 

The mainland Greeks had hoped that the Persian navy and the Greek commander Memnon would land in Greece and help them launch a rebellion against Antipater's Macedonians, transfer the war into Macedonia itself, and cut off Alexander in Asia, but the sealing of the coast prevented this from happening.  Memnon fell sick and died while attempting to regain the lost Greek city of Miletus on the Asia Minor coast, and the Persian plan to transfer the war into Europe well apart.

At Tyre, Alexander received reinforcements from Europe, reorganized his forces, and started for Babylon. He conquered the lands between rivers Tigris and Euphrates and found the Persian army at the plains of Gaugamela, near modern Irbil in Iraq, which according to the exaggerated accounts of antiquity was said to number a million men. The Macedonians spotted the lights from the Persian campfires and encouraged Alexander to lead his attack under cover of darkness. But he refused to take advantage of the situation because he wanted to defeat Darius in an equally matched battle so that the Persian king would never again dare to raise an army against him.

The two armies met on the battlefield the next morning, October 1, 331 BC.  On the Persian side were numerous Asiatic nations - Bactrians, Indians, Medians, Sogdians, even Albanians from the Caucasus, the ancestors of the modern Albanians who many centuries later migrated to Europe and are now northern neighbors to the modern Greeks and western neighbors to the modern Macedonians.  The survivors of the 50,000 Greeks which Darius had on his side at the beginning of the war were also among the Persian ranks.

At the beginning of the battle the Persian forces split and separated the two Macedonians wings. The wing of general Parmenio appeared to be backing down, but Alexander's cavalry rode straight after Darius and forced again his flight like he did at Issus. Darius fled to Ecbatana in Media, and Alexander occupied Babylon, the imperial capital Susa, and the Persian capital Persepolis, and was henceforth proclaimed king of Asia. Four months later, the Macedonians burned the royal palace in Persepolis, completing the end of the ancient Persian Empire.

Meanwhile in Greece, the Greeks under the leadership of Sparta rose to a rebellion against the Macedonian occupation.Antipater was in Thrace at the time and the Greeks took the opportunity to push back the Macedonian forces.  But their initial victory did not last for long as Antipater returned with a large army, defeated the rebels, and regained Greece.  5,300 Greeks, including the Spartan king Agis were killed, while the Macedonians lost 3,500 men.

In Asia, the news of the beginning of the Greek rebellion had Alexander so deeply worried, that he immediately sent money to Antipater to counter it.  And when he learned that the Greeks were defeated, he proclaimed the end of the "Hellenic Crusade" and discharged all-Greek forces in his army. He no longer needed these hostages and troublemakers.

To win the support of the Persian aristocracy Alexander appointed many Persians as provincial governors in his new empire.  He adopted the Persian dress for ceremonies, gave orders for Persians to be enlisted in the army, and encouraged the Macedonians to marry Persian women.   

But the Macedonians were unhappy with Alexander's Orientalization for they were proud of their Macedonian customs, culture, and language.  His increasingly Oriental behavior eventually led to conflict with the Macedonian nobles and some Greeks in the train. In 330 BC series of allegations were brought up against some of Alexander's officers concerning a plot to murder him. Alexander tortured and executed the accused leader of the conspiracy, Parmenio's son Philotas, the commander of the cavalry. Several other officers were also executed according to Macedonian law, in order to eliminate the alleged attempt on Alexander's life. During the trial of Philotas Alexander raised the question of the use of the ancient Macedonian language. He spoke:

"'The Macedonians are about to pass judgment upon you; I wish to know whether you will use their native tongue in addressing them.' Philotas replied: 'Besides the Macedonians there are many present who, I think, will more easily understand what I shall say if I use the same language which you have employed.' Than said the king: 'Do you not see how Philotas loathes even the language of his fatherland? For he alone disdains to learn it. But let him by all means speak in whatever way he desires, provided that you remember that he holds out customs in as much abhorrence as our language.'" (Quintus Curtius Rufus 6.9.34-36)

The trial of Philotas took place in Asia before a multiethnic public, which has accepted Greek as their common language. Alexander spoke Macedonian with his conationals, but used Greek in addressing the Greeks and the Asians, as Greek was widely taken as international language in ancient times.  Like Carthaginian, Illyrian, and Thracian, ancient Macedonian was not recorded in writing. However, on the bases of about hundred glosses, Macedonian words noted and explained by Greek writers, some place names from Macedonia, and names of individuals, most scholars believe that ancient Macedonian was a separate Indo-European language. Evidence from phonology indicates that the ancient Macedonian language was distinct from ancient Greek and closer to the Thracian and Illyrian languages. Some modern writers have erroneously concluded that the Macedonians spoke Greek based on few Greek inscriptions discovered in Macedonia, but that is by no means a proof that the Macedonian was not a distinct language.  Greek inscriptions were also found in Thrace and Illyria, the Thracians even inscribed their coins and vessels in Greek, and we know that both the Illyrians and the Thracians were not Greeks who had distinct languages.

After Philotas was executed according to the Macedonian custom, Alexander ordered next the execution of Philotas' father, general Parmenio.  But the death of the old general did not sit well with every Macedonian in the army.  Parmenio was a veteran, proven solder of Philip's guard, a men who played a major part in leading the Macedonian armies and rising the country to a world power. In fact Philip II had often remarked how proud he was to have Parmenio as his general.  

Alexander next killed Cleitus, another Macedonian noble, in a drunken brawl. Heavy drinking was a cherished tradition at the Macedonian court and that day Cleitus publicly denounced the king before the present for the murders of Parmenio and Philotas. He went further by ridiculing Alexander for claiming to be "son of Ammon" and for denouncing his own father Philip II.  Alexander lost his temper, snatched the spear from the bodyguard standing near, and ran Cleitus through with it. Although he mourned his friend excessively and nearly committed suicide when he realized what he had done, all of Alexander's associates thereafter feared his paranoia and dangerous temper.

He next demanded that Europeans, just like the Asians, follow the Oriental etiquette of prostrating themselves before the king - which he knew was regarded as an act of worship by the Greeks. But resistance put by Macedonian officers and by the Greek historian Callisthenes, the nephew of Aristotle who had joined the expedition, defeated the attempt. Callisthenes was soon executed on a charge of conspiracy, and we can only imagine how Aristotle received the news of his death.  The two were already estranged for a long time before Callisthenes’ execution, as Alexander's letters to his former tutor carried unfriendly contents.

The Macedonians spent two hard years in Bactria fighting a guerilla war against the followers of Bessus and the Sogdian ruler Spitamenes.  Finally, Bessus was caught and executed for the murder of his king Darius III, and Spitamenes was killed by his own wife which was tired of running away. Bactria and Sogdiana, the most eastern provinces of the Persian Empire came under Macedonian control.  It is here that Alexander fell in love with and married the beautiful Sogdian princess Roxane.

One of the villages in which the army stopped belonged to the Malli, who were said to be one of the most warlike of the Indian tribes. Alexander was severally wounded in this attack when an arrow pierced his breastplate and his ribcage.  The Macedonians rescued him in a narrow escape from the village. Still the Malli surrendered as Alexander became to recover from the grave wound.  The travel down the river resumed and the Macedonian army reached the mouth of the Indus in the summer of 325 BC. Then it turned westward to Persia.

But the return was a disaster.  The army was marching through the notorious Gerdosian desert during the middle of the summer. By the time Alexander reached Susa thousands had died of heat and exhaustion.

After his death, nearly all the noble Susa marriages dissolved, which shows that the Macedonians despised the idea. There never came to unity between Macedonians and Persians and there wasn't even a unity among the Macedonians.  Alexander's death opened the anarchic age of the Successors and a bloody Macedonian civil war for power followed. 

As soon as the news of Alexander's death were known, the Greeks rebelled yet again and so begun the Lamian war.The Macedonians were defeated and expelled from Greece, but then Antipater received reinforcements from Craterus who brought to Macedonia the 10,000 veterans discharged at Opis.  Antipater and Craterus jointly marched into Greece, defeated the Greek army at Crannon in Thessaly and brought the war to an end. Greece will remain under Macedonian rule for the next one and a half century.

In Asia the Macedonian commanders who served Alexander fought each other for power.Perdiccas and Meleager were murdered,Antigonus rose to control most of Asia, but his growth of power brought the other Macedonian generals in coalition against him.  He was killed in battle and the Macedonian Empire split into four main kingdoms - the one of Seleucus(Asia),Ptolemy(Egypt),Lysimachus (Thrace), and Antipater's son Cassander (Macedonia, including Greece).