Alexander never got along well with his father, although Philip was proud of Alexander for the Bucephalus incident. Alexander had always been closer to Olympia than to Philip. Their relations did not get along all that well, owing primarily to Olympia's non-Macedonian heritage. The family essentially was split apart irreparably when Philip married a woman named Cleopatra, a Macedonian. At the wedding banquet, Cleopatra's father made a remark about Philip fathering a "legitimate" heir, i.e., one that was pure Macedonian. Alexander took exception and threw his cup at the man, and some sources say Alexander killed him. Enraged, Philip stood up and charged at Alexander, only to trip and fall on his face in his drunken stupor. Alexander, rather upset at the scene, is to have shouted:

"Here is the man who was making ready to cross from Europe to Asia, and who cannot even cross from one table to another without losing his balance."

When Philip divorced Olympia Alexander fled. Although allowed to return, he remained isolated until Philip was assassinated (some think that Olympia may have even had a role in Philip's murder), in the summer of 336 BC.

Alexander the Great inherited the Macedonian throne when his father was killed. Once in power, he disposed quickly of all conspirators and domestic enemies by ordering their execution. Then he descended on Thessaly, where partisans of independence had gained ascendancy, and restored Macedonian rule. Before the end of the summer of 336 BC he had re-established his position in Greece and was elected by a congress of states at Corinth. But, Greek cities, like Athens and Thebes, which had pledged allegiance to Philip, were unsure if they wished to do the same for a twenty-year-old boy. Moreover, the Hellenes considered Macedonian domination in the Greek states as an alien rule, imported from outside by the members of other tribes, the, as Plutarch says, allophyloi (Plutarchus, Vita Arati, 16). Likewise, northern barbarians that Philip had subdued were threatening to break away from Macedonia and wreak havoc in the north. Alexander's advisors suggested that he let Athens and Thebes go and to be gentle with the barbarians to prevent a revolt. However, in 335 BC, Alexander campaigned toward the Danube, to secure Macedonia's northern frontier. He carried out a successful campaign against the defecting Thracians, penetrating to the Danube River. Alexander marched quickly north and drove the rebelling barbarians beyond the Danube River and out of the way. On his return he crushed in a single week the threatening Illyrians

Alexander began his campaign against Persia in the spring of 334 BC by crossing the Hellespont (modern Dardanelles) with an army of 35,000 Macedonians and 7,600 Greeks. He threw his spear from his ship to the coast and it stuck in the ground. He stepped onto the shore, pulled his weapon from the soil, and declared that the whole of Asia would be won by the spear. His chief officers, were all Macedonians, included Antigonus, Ptolemy, and Seleucus.

The Macedonian army soon encountered the Persian army under King Darius III at the crossing of the river Granicus, near the ancient city of Troy. Alexander attacked an army of Persians and Greek hoplites (a heavily armed foot soldiers of ancient Greece) who distinguished themselves on the side of the Persians against the Macedonians. Alexander'sforces defeated the enemy (totaling 40,000 men) and, according to tradition, lost only 110 men.

Then he turned northward to Gordion, home of the famous Gordian Knot. The legend behind the ancient knot was that the man who could untie it was destined to rule the entire world. Alexander simply slashed the knot with his sword and unravelled it.

In November of 333 BC, Alexander met Darius in battle for the second time at a mountain pass at Issus, in north-eastern Syria. Although the Persian army greatly outnumbered the Macedonians, the narrow field of battle allowed Alexander to defeat the Persians. The Battle of Issus ended in a great victory for Alexander. Cut off from his base, Darius fled northward, abandoning his mother, wife, and children to Alexander, who treated them with the respect due to royalty.

In the next year, Alexander marched down the Phoenician coast and received the surrenders of all of the major cities there except for Tyre. A seven-month siege of the city followed, and the Tyrians eventually surrendered to Alexander. Then he continued south into Egypt after he had secured the entire Aegean coast.

Continuing his campaign to conquer the world, Alexander entered Egypt in 331 BC. When he arrived, he was welcomed, and he ordered a city to be designed and founded in his name at the mouth of the river Nile. Alexandria would become one of the major cultural centres in the Mediterranean world in the following centuries.

In the spring of 331 Alexander made a pilgrimage to the great temple and oracle of Amon-Ra, Egyptian god of the sun, the Egyptian pharaohs were believed to be sons of Amon-Ra and Alexander, the new ruler of Egypt, wanted the god to acknowledge him as his son.

While staying in Egypt, Alexander spontaneously decided to make a dangerous trip across the desert to visit the oracle at the temple of Zeus Ammon. The legend says that on the way he was blessed with abundant rain, and he was guided across the desert by ravens. At the temple, Alexander spoke to the oracle about matters that are unclear to most historians. Again, the rumours speculate that the priest told Alexander that he was the son of Zeus Ammon and that he was destined to rule the world.
 
He was then made pharaoh voluntarily by the Egyptians, who despised living under Persian rule. He exchanged letters with Darius while he was in Egypt, and the Persian offered a truce with Alexander with a gift of several western provinces of the Persian Empire, but Alexander refused to make peace unless he could have the whole empire. In the middle of 331 BC Alexander marched back to Persia to find Darius.

For the purpose of the new campaign, Alexander reorganized his forces at Tyre and started for Babylon with an army of 40,000 infantry and around 7000 cavalry. He found the Persian army which, according to the exaggerated accounts was said to be a number of million men at the plains of Gaugamela (near modern Irbil, Iraq). The Macedonians spotted the lights from Persian campfires one night, and they encouraged Alexander to lead his attack under the cover of darkness. He refused to take advantage of their 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 the Macedonians. The two armies met on the battlefield the next morning on October 1, in ther year of 331 BC, and the Macedonian forces swept through the Persian army and slaughtered them. Darius fled as he had done at Issus to the mountain residence of Ecbatana, while Alexander occupied Babylon, the imperial capital Susa, and Persepolis. Consequently Alexander was proclaimed king of Persia, and to win the support of the Persian aristocracy he appointed mainly Persians as provincial governors. After four months, the Macedonians burned the royal palace to the ground thus completing the end of the ancient Persian Empire.

Alexander continued his pursuit of Darius for hundreds of miles from Persepolis. He found the Persian king dead in his coach, assassinated by his own men. Alexander had the assassin executed and gave Darius a royal funeral.

During the reign of Alexander the Great, the Macedonians spoke their own native language, as the native language of Alexander the Great was not understood by the ancient Greeks (Quintus Curtius Rufus, VI, 9, 37 ). Similarly, Plutarch points out that Alexander spoke to his fellow countrymen in Macedonian: "he [Alexander] called out aloud to his guards in the Macedonian language, which was a certain sign of some great disturbance in him" (Plutarch, Alexander, 51). Still, Alexander spoke also Greek, loved Homer, and respected his tutor Aristotle. At the same time though, there is much evidence that generally he was not fond of the Greeks of his day. The chronicler Curtius, describing the atmosphere before a battle, gave a notion of the different attitudes of the great commander, who applied the principle of identity to every ethnic group in his army. In respect to the various motives for taking part in that war, Curtius wrote:

"Riding to the front line he [Alexander the Great] named the soldiers and they responded from spot to spot where they were lined up. The Macedonians, who had won so many battles in Europe and set off to invade Asia ... got encouragement from him - he reminded them of their permanent values. They were the world's liberators and one day they would pass the frontiers set by Hercules and Patter Liber. They would subdue all races on Earth. Bactrius and India would become Macedonian provinces. Getting closer to the Greeks, he reminded them that those were the people who provoked war with Greece, ... those were the people that burned their temples and cities ... As the Illirians and Trakians lived mainly from plunder, he told them to look at the enemy line glittering in gold ..."

Q. C. Rufus, Alexander III, 10, 4-10