In the spring of 333 Alexander pursued his march eastwards, and on arriving at Ancyra received the submission of the Paphlagonians. He then advanced through Cappadocia without resistance; and forcing his way through the passes of Mount Taurus (the PYLAE CILICIAE), he descended into the plains of Cilicia. Hence he pushed on rapidly to Tarsus, which he found abandoned by the enemy. Whilst still heated with the march Alexander plunged into the clear but cold stream of the Cydnus, which runs by the town. The result was a fever, which soon became so violent as to threaten his life. An Acarnanian physician, named Philip, who accompanied him, prescribed a remedy; but at the same time Alexander received a letter informing him that Philip had been bribed by Darius, the Persian king, to poison him. He had however, too much confidence in the trusty Philip to believe the accusation and handed him the letter whilst he drank the draught. Either the medicine, or Alexander's youthful constitution, at length triumphed over the disorder. After remaining some time at Tarsus, he continued his march along the coast to Mallus, where he first received certain tidings of the great Persian army, commanded by Darius in person. It is said to have consisted of 600,000 fighting men, besides all that train of attendants which usually accompanied the march of a Persian monarch. Alexander found Darius encamped near Issus on the right bank of the little river Pinarus. The Persian king could hardly have been caught in a more unfavourable position, since the narrow and rugged plain between Mount Amanus and the sea afforded no scope for the evolutions of large bodies, and thus entirely deprived him of the advantage of his numerical superiority. Alexander occupied the pass between Syria and Cilicia at midnight, and at daybreak began to descend into the plain of the Pinarus, ordering his troops to deploy into line as the ground expanded and thus to arrive in battle-array before the Persians. Darius had thrown 30,000 cavalry and 20,000 infantry across the river, to check the advance of the Macedonians; whilst on the right bank were drawn up his choicest Persian troops to the number of 60,000, together with 30,000 Greek mercenaries, who formed the centre, and on whom he chiefly relied. These, it appears, were all that the breadth of the plain allowed to be drawn up in line. The remainder of the vast host were posted in separate bodies in the farther parts of the plain, and were unable to take any share in the combat. Darius placed himself in the centre of the line in a magnificent state chariot. The banks of the Pinarus were in many parts steep, and where they were level Darius had caused them to be intrenched. As Alexander advanced, the Persian cavalry which had been thrown across the river were recalled; but the 20,000 infantry had been driven into the mountains, where Alexander held them in check with a small body of horse. The left wing of the Macedonians, under the command of Parmenio, was ordered to keep near the sea, to prevent being outflanked. The right wing was led by Alexander in person, who rushed impetuously into the water, and was soon engaged in close combat with the Persians. The latter were immediately routed; but what chiefly decided the fortune of the day was the timidity of Darius himself, who, on beholding the defeat of his left wing, immediately took to flight. His example was followed by his whole army. One hundred thousand Persians are said to have been left upon the field. On reaching the hills Darius threw aside his royal robes his bow and shield, and, mounting a fleet courser, was soon out of reach of pursuit. The Persian camp became the spoil of the Macedonians; but the tent of Darius, together with his chariot, robes, and arms, was reserved for Alexander himself. It was now that the Macedonian king first had ocular proof of the nature of Eastern royalty. One compartment of the tent of Darius had been fitted up as a bath, which steamed with the richest odours; whilst another presented a magnificent pavilion, containing a table richly spread for the banquet of Darius. But from an adjoining tent issued the wail of female voices, where Sisygambis the mother, and Statira the wife of Darius, were lamenting the supposed death of the Persian monarch. Alexander sent to assure them of his safety, and ordered them to be treated with the most delicate and respectful attention.

Such was the memorable battle of Issus, fought in November, B.C. 333. A large treasure which Parmenio was sent forward with a detachment to seize, fell into the hands of the Macedonians at Damascus. Another favourable result of the victory was that it suppressed some attempts at revolt from the Macedonian power, which with the support of Persia, had been manifested in Greece. But, in order to put a complete stop to all such intrigues, which chiefly depended on the assistance of a Persian fleet, Alexander resolved to seize Phoenicia and Egypt, and thus to strike at the root of the Persian maritime power.

Meanwhile, Darius, attended by a body of only 4000 fugitives, had crossed the Euphrates at Thapsacus. Before he had set out from Babylon the whole forces of the empire had been summoned; but he had not thought it worth while to wait for what he deemed a merely useless encumbrance; and the more distant levies, which comprised some of the best troops of the empire, were still hastening towards Babylon. In a short time, therefore, he would be at the head of a still more numerous host than that which had fought at Issus; yet he thought it safer to open negotiations with Alexander than to trust to the chance of arms. With this view he sent a letter to Alexander, who was now at Marathus in Phoenicia, proposing to become his friend and ally; but Alexander rejected all his overtures, and told him that he must in future be addressed not in the language of an equal, but of a subject.