Alexander of Macedon received a large and varied inheritance from his father, Philip. Perhaps the most valuable item was the army that Philip had built to enable the creation of an expansive state reaching from the Adriatic to the Black Sea and from Balkans through mainland Greece. Equally valuable for Alexander's career was his father's plan to lead this army against the Persians; the effort was already underway at the time of Philip's murder in 336 BCE. Within two years of his father's death, Alexander and a force of 30,000 infantry and 5000 cavalry crossed the Dardanelles into Anatolia, allegedly to avenge the Greeks on the Persians in retaliation for the attempt to add Greece to the Persian Empire in the early fifth century.

The Macedonian success was overwhelming and of lightning speed. By 322, the Persian king offered to cede all Persian territory west of the Euphrates. When Alexander pondered the offer with his council of generals, a senior officer named Parmenio advised, "If I were Alexander, I would accept the terms." Alexander is reported to have answered, "If I were Parmenio, that is what I would do. But I am Alexander and so will answer in another way." That answer was to press further east. The Macedonians defeated a massive Persian effort in northern Mesopotamia, then, without a battle, received Babylon from its Persian satrap. Alexander then moved on to take command of the Persian capitols at Susa and Persepolis, where he sat on the throne of the Persian kings and so became Great King in 330.

But he did not stop here. Rather he struck out for the northeastern boundary of the Persian Empire into what is now modern Afghanistan, Baluchistan and Samarkand. Even success in these lands was insufficient for Alexander; the Macedonians continued to march, some down the Khyber Pass, the rest through the hill country in the northern Indus valley to regroup in western India. Victorious against Mauryan Indian troops with their frightening corps of elephants, Alexander encouraged his Macedonians to travel eastward to find even greater challenges and wonders. When they refused, Alexander was forced to return to Babylon.

Alexander's men were amazed by the splendor of Babylon, and in India found that "those who bring exports from India to our country purchase these jewels at great price and export them, and all Greeks in old time, and Romans now who are rich and prosperous, are more eager to buy the sea pearl" (The Indica VIII.8.9). That the richness of India was already known is indicated by an exploration of the trade-routes to India undertaken two centuries earlier at the behest of the Persian King, Darius I. Now Alexander equipped a fleet to carry some of his troops from the mouth of the Indus River to the head of the Persian Gulf to learn the feasibility of sailing from Mesopotamia to India.

In addition to experiencing and appreciating the fruits of the Silk Road, Alexander helped to shape its future through his policy of establishing settlements in regions the Macedonians had conquered. Settlements in the easternmost region of his conquests endured to become Indo-Greek kingships in Bactria and northern India. Initially linked with the western empire, their culture was essentially Greek. Over the nearly two centuries as they were increasingly isolated from the west, eastern elements became more dominant. The Greek goddess Athena decorated the coinage of one of those kings, Menander, who ruled in the middle of the second century, even though Menander was a convert to Buddhism. Even in its origins, then, the Silk Road mingled cultures as well as products.