Ishizu's family have been guarding Pharaoh Atem's tomb (Yami-Yugi) for generations. Marik no longer wanted to become a Tomb Keeper and when he was forced to take the initiation ritual to become a full Tomb Keeper, he unwillingly unleashed Yami Marik, who took the Millennium Rod for himself.
In the Japanese anime he killed his father to stop him from killing Rishid. In the English anime he sent his father to the Shadow Realm. Regardless, Yami Marik was sealed away in Marik's body by Odion.
Ishizu is the Secretary General of the Egyptian Supreme Council of Antiquities. She became a museum curator in order to lure Yugi Muto and Seto Kaiba in order to save Marik from his darker alter ego, Yami Marik.
She gave Kaiba "Obelisk The Tormentor" in exchange for him starting the Battle City tournament, where he could acquire the remaining God Cards, but told him that regardless he would end up returning the card. She had predicted this using the power of her Millennium Necklace.
Ishizu qualifies to the Battle City quarter-finals, where she duels Kaiba. She predicts all of Kaiba's moves and foresees her victory, but a vision of Kisara compels Kaiba to summon "Blue-Eyes White Dragon" instead of Obelisk.
Kaiba claims to make his own future and tributes "Obelisk the Tormentor" and "Gadget Soldier" to summon Blue-Eyes White Dragon, hence avoiding his predicted defeat. Following her loss, Ishizu gives the Millennium Necklace to Yugi, claiming that it is no longer necessary as the future it predicts is not infallible and can be changed.
During the finals where Yugi faced Marik, Odion convinces Marik to accept responsibility, freeing him from Yami Marik. Ishizu and Marik are then able to fulfill their duties as Tomb Keepers, by revealing the Pharaoh's memory which had been carved (Tattooed in the English anime) onto Marik's back. Ishizu, Marik and Odion then return to Egypt to start a new life.
After the Pharaoh recovers his memories and his name in the Dawn of the Duel arc, Ishizu, Marik and Odion lead Yugi and his friends to the tomb of the Pharaoh in order for Pharaoh Atem and Yugi to have a final duel in order to determine if the spirit will move on to the afterlife or remain in the present for another 5,000 years.
When the duel is over and the tomb is destroyed, Ishizu states that her family's duties as the Pharaoh's Tomb Keepers are finally complete since his spirit has returned to the nether world and the Millennium Items have been sealed forever.