The Battle of Issus again featured the Persians (led by King Darius) and the Macedonians (led by King Alexander the Great). The King of Macedonia's advisors advised him to marshal his troops at Issus, where he would wait for King Darius. There he waited in a narrow passage between the mountains and the sea. He waited there because there was less of a chance that Alexander would be outflanked. Alexander could also Darius from whichever pass he came through. Alexander anticipated that Darius would come through the Syrian Gates. For that reason he left Issus to Myriandrus, To wait for the enemy that never came.

This was the chance that Darius was waiting for. While Alexander was held up by a violent thunderstorm at Myriandrus, Darius set out for the Amanic Gates (modern day Bogtche Pass). After passing through the gate unharmed, he set out from Castabala to Issus. He captured most of Alexander's Hospital Cases at Issus, cut off their hands, and seared them with pitch.

Alexander and his men fought through Indian monsoon rains just to get Darius at Issus. Meanwhile, Darius took Alexander's men on a tour of the Persian camp and then sent them on their way. They were instructed to report to Alexander what they had seen. Darius then went from Issus to the Pinarus River. The Macedonian army caught up with Darius and his army at the Pinarus River. By the time Darius had his Infantry into battle-formation, it was mid-afternoon and Alexander's army was getting dangerously close. Darius saw that Alexander had to make last minute reorganizations of his front line, which gave him enough time to move his best squadrons to the front line.

Alexander and his men went after Darius when Alexander found out that his men were out of trouble. But everything was against him. For one, Darius had a half-mile start ahead of them. The route that Darius had taken was also crammed with the remnants of the Persian Imperial Army. Nevertheless, Alexander followed Darius for twenty-five miles before returning back to camp in the dark.