From the beginning of his life, Alexander was taught to see Persians as barbarians to be conquered. Aristotle himself believed that non-Greeks were meant to be slaves; he therefore encouraged Alexander to be a friend to his countrymen and a despot to others. This xenophobia fueled Alexander's desire for conquest, as he was taught that his mission was grounded in a kind of natural law.

However, Alexander would eventually depart from his old master's attitude. As he conquered various Persian territories, he saw that it would more practical to install Persian rather than Macedonian satraps, in order to secure their loyalty. Gradually, as a result of these working relationships, he apparently developed a respect for the Persian way of life and saw that, for all parties involved, cooperation would be better than attempted enslavement. Moreover, Alexander's indulgence in the exotic luxuries of Persia may have contributed to his change of heart. His new attitudes toward the Persians made him unpopular among conservative Macedonians, however, who disliked living as equals with Persians and resented Alexander's favorable treatment of them. This resentment increased when Alexander attempted to fuse his two kingdoms through various policies, such as the requirement that subjects prostrate themselves before his feet–previously common in Persia but alien and offensive to the Greeks.

Alexander was ruthless in his treatment of potential opponents. Such behavior might seem paranoid and severe by modern standards, but it can be argued that in Alexander's time it was a necessity. Legitimate conspiracies did arise, as a king often had several potential rivals for the throne. Moreover, Alexander knew there were specific reasons for his unpopularity–namely, his favorable attitude toward Persia and his status as Hegemon in a reluctantly ruled Greece. Alexander's enemies and potential enemies, therefore, were not hard to identify, as he saw ambition and hatred in all of them.

In dealing with such enemies, he would first try to isolate them by removing or somehow disrupting their allies, so that the enemies' influence would be weakened. Then, if necessary, he would find an excuse for the enemies' execution. Two famous cases–that of Philotas and his father, Parmenion, as well as that of Callisthenes–were based on such an association with conspiracy. The cases in fact are very similar. In both cases, Alexander exposed a conspiracy that he could trace, however dubiously, back to the offending party. A farcical trial took place in front of the army, and the executions were ordered with no objections. Such a fate could be reserved for anyone, no matter how loyal he had been in the past. Even Alexander's early adviser, Antipater, would surely have faced this fate if Alexander had not died first.

Alexander's rule over the Hellenic League was always unstable, as Philip's had been before him. The other Greek states viewed Macedonia with resentment. Before Philip's ascent, Macedonia had been considered semi-barbaric; when he defeated Athens and Thebes at Chaeronea, they submitted only because it was necessary to do so at the time. The other Greek states, despite swearing allegiances, resented Macedonian rule and were constantly plotting against it.

Alexander therefore faced the constant threat of a Greek rebellion while he was out conquering Asia. Indeed, early on, when it looked like Darius might defeat Alexander, the Greeks began plotting an uprising against the Macedonians. Alexander had to use considerable muscle just to keep the Hellenic League in check after Philip's death, and Alexander was never forgiven for his razing of Thebes. Indeed, Neither Alexander nor Philip ever gained the sincere loyalty of his subjects. During the early stages of the war, Darius was in regular contact with Athens for possible aid. Moreover, the Persian army against which that Alexander fought consisted largely of Greek mercenaries; when Alexander defeated them, the mercenaries' native cities sympathized with the Persians' loss.