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Fall to Alexander III of Macedon

Artaxerxes III was succeeded by Artaxerxes IV Arses, who before he could act was also poisoned by Bagoas. Bagoas is further said to have killed not only all Arses' children, but many of the other princes of the land. Bagoas then placed Darius III, a nephew of Artaxerxes IV, on the throne. Darius III, previously the Satrap of Armenia, personally forced Bagoas to swallow poison. In 334 BC, when Darius was just succeeding in subduing Egypt again, Alexander and his battle-hardened troops invaded Asia Minor.

Alexander the Great (Alexander III of Macedon) defeated the Persian armies at Granicus (334 BC), followed by Issus (333 BC), and lastly at Gaugamela (331 BC). Afterwards, he marched on Susa and Persepolis which surrendered in early 330 BC. From Persepolis, Alexander headed north to Pasargadae, where he visited the tomb of Cyrus, the man whom he had heard of from the Cyropaedia.

In the ensuing chaos created by Alexander's invasion of Persia, Cyrus's tomb was broken into and most of its luxuries were looted. When Alexander reached the tomb, he was horrified by the manner in which it had been treated, and questioned the Magi, putting them on trial. By some accounts, Alexander's decision to put the Magi on trial was more an attempt to undermine their influence and display his own power than a show of concern for Cyrus's tomb. Regardless, Alexander the Great ordered Aristobulus to improve the tomb's condition and restore its interior, showing respect for Cyrus. From there he headed to Ecbatana, where Darius III had sought refuge.

Darius III was taken prisoner by Bessus, his Bactrian satrap and kinsman. As Alexander approached, Bessus had his men murder Darius III and then declared himself Darius' successor, as Artaxerxes V, before retreating into Central Asia leaving Darius' body in the road to delay Alexander, who brought it to Persepolis for an honourable funeral. Bessus would then create a coalition of his forces, to create an army to defend against Alexander. Before Bessus could fully unite with his confederates at the eastern part of the empire, Alexander, fearing the danger of Bessus gaining control, found him, put him on trial in a Persian court under his control, and ordered his execution in a "cruel and barbarous manner."

Alexander generally kept the original Achaemenid administrative structure, leading some scholars to dub him as "the last of the Achaemenids". Upon Alexander's death in 323 BC, his empire was divided among his generals, the Diadochi, resulting in a number of smaller states. The largest of these, which held sway over the Iranian plateau, was the Seleucid Empire, ruled by Alexander's general Seleucus I Nicator. Native Iranian rule would be restored by the Parthians of northeastern Iran over the course of the 2nd century BC through the Parthian Empire.