After leaving his mother with her brother, King Alexander of Epirus (to whom Philip had given the throne after ousting Arrybas), Alexander went north to reside among the wild tribes of Illyria. There he began stirring up agitation against his father, while his mother tried to incite her brother to take revenge against Philip.

While they were away, however, Philip's new wife, Cleopatra, became pregnant, which made Alexander's hopes appear increasingly grim. When the child turned out to be a girl, however, Philip had to reconsider his plans and brought Alexander back. Though Olympias was not invited to return, Alexander did go back to Macedonia. The relationship between father and son, however, remained full of suspicion.

When Philip heard that Olympias had succeeded in convincing her brother to declare war on Macedonia, he chose not to allow himself to get sidetracked with minor battles. Instead, he used diplomacy and offered the King of Epirus the hand of Cleopatra, the daughter of Philip and Olympias and therefore the King's niece. Perhaps reluctant to follow through with an attack, the King of Epirus accepted the offer, leaving Olympias was thwarted for the time being.

The tense domestic situation in Macedonia gave rise to another conflict between father and son. Pixodarus, ruler of Caria, hoped to secure his position in Asia in the event that Macedonia did succeed against Persia; Philip saw this as a welcome addition to his Asian forces. Therefore, arrangements were begun for the marriage of Philip's daughter and Philip Arrhidaeus, Alexander's mentally disabled half-brother. Alexander somehow interpreted this arrangement as a threat to his succession–unlikely, as Philip would not have entrusted the throne to his incapable son–and in response he sent his friend Thessalus to offer to switch the engagement to Alexander himself. When Philip found out, he was furious, outraged that Alexander had thought to become the son-in-law of a barbarian king.

Thessalus, who had fled to Corinth, was extradited and brought to Macedonia in chains. Several of Alexander's friends, including Ptolemy, Harpalus, Nearchus, Erigyius, and Laeomedon, were exiled. Although Alexander would later release Thessalus and recall his friends, who would all serve him faithfully, Philip's actions had clear implications. He hoped to isolate Alexander to prevent the possibility of any conspiracies developing. Cleopatra was due to give birth to a second child, and Alexander's anxieties returned.

Philip, of course, could not have been happier. The prospects for a Persian invasion were looking better than ever before, and he had begun preparations for a lavish wedding celebration for his daughter and the King of Epirus. He hoped to use this opportunity to impress the Greek leaders in attendance, in an attempt to win their genuine support. When Philip's wife Cleopatra gave birth to a son, Philip named him Caranus, after the mythical founder of the Argead dynasty to which Philip belonged. Alexander had great reason for concern, but with his mother's return to Macedonia for the wedding, he now had a strong ally.

The wedding was indeed a grand affair, though Philip may have irked more than a few attendees by placing a statue of himself among the figures of the twelve Olympian gods. On the second day, Philip prepared his ceremonial entrance, walking between Alexander his son and Alexander his new son-in-law. Philip instructed his bodyguards to follow at a distance, as he wanted to show that he was protected by the goodwill of the Greeks. However, as he paused at the entrance of the arena, a man–who was himself a member of Philip's bodyguard–drew his sword and stabbed Philip through his ribs, killing him instantly. Though the assassin had a good head start on his pursuers, he tripped and was killed, reportedly on the spot.

The assassin's name was Pausanias; speculations about his motive remain uncertain. The generally accepted story is that he was a former lover of Philip's, and that through various plot twists he ended up offending Attalus, who avenged himself through a public rape of Pausanias with his friends joining in. When Pausanias recovered and appealed to Philip, the latter took no action, for fear of alienating Attalus and his powerful faction. This alone, however, seems insufficient to explain Pausanias's action–why he chose Philip rather than Attalus, and why he chose this particular day when he had plenty of opportunities as a bodyguard to carry out the revenge.

Suspicion therefore turns to Olympias. Indeed, her subsequent behavior–including an annual visit to offer sacrifices over Pausanias's grave on the anniversary of his deed–do implicate her. Most agree that, at the very least, she incited Pausanias's anger and encouraged the assassination; she also may have offered Pausanias protection and helped to arrange his escape. Although no direct evidence links Alexander to this conspiracy, it is unlikely that Olympias would have proceeded without consulting him.

Afterward, Alexander circulated the theory that Pausanias was a paid agent of Persia, who hoped to prevent or at least postpone a Macedonian invasion. Both Alexander's contemporaries and modern writers have dismissed this theory as propaganda. Some have even called into question whether the Attalus story is true, as Attalus, who had always been one of Alexander's bitter enemies, was murdered shortly thereafter in Asia, on Alexander's orders. Furthermore, the three men who killed Pausanias were close allies of Alexander, and they may have acted abruptly in order to silence him, when it would have made more sense to arrest and question him first. Thus, although the degree of culpability cannot be determined precisely, most scholars seem comfortable in the belief that Alexander became king through patricide.