The dynasty was founded by Ahmose I, the brother of Kamose, the last ruler of the Seventeenth Dynasty. Ahmose finished the campaign to expel the hated Hyksos rulers. With this dynasty, the Second Intermediate Period ended, and the New Kingdom or the Egyptian Empire began. Highlights of this dynasty include: Queen Hatshepsut, who effectively ruled during the minority of her stepson, but was later considered a usurper; the first formal relations with foreign countries under Amenhotep III, of which some records were included in the el Amarna letters; and Akhenaten, who instigated the earliest verified expression of monotheism, (although the actual origins of monotheism are the subject of continuing research and debate). Scholars believe that Akhenaten's devotion to his God Aten offended many in power, which contributed to the end of this dynasty; he later suffered damnatio memoriae. Although modern students of Egyptology consider the monotheism of Akhenaten the most important event of this period, the Egyptians themselves considered the so-called Amarna period an unfortunate aberration.

The dynasty's final years were clearly shaky: the unidentified widow of King Nibhururiya (identified with either Akhenaten or Tutankhamun) wrote to Suppiluliumas I, king of the Hittites, asking him to send one of his sons to be her husband and rule Egypt. Suppiluliumas sent an ambassador to investigate, who reported that the situation was accurately described; however the destined Hittite prince Zannanza was murdered en route on the borders between the Hittite and Egyptian Empires, and the last two members of this dynasty – Ay and Horemheb – came from officials of the royal court. Suppiluliumas I reacted with rage at the news of his son's death by going to war against Egypt's vassal states in Syria and Northern Canaan and captured the city of Amki. Unfortunately, Egyptian prisoners of war from Amki carried a plague which would eventually ravage the Hittite Empire and kill both Suppiluliumas I and his direct successor.

The Nineteenth Dynasty of Ramesses I succeeded it in 1292 BC.

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