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Zaku and his team were ordered to find and kill Uchiha Sasuke. Unfortunately Orochimaru merely used the team as fodder to test Sasuke's powers after he placed a cursed seal on him. When Zaku and his team began to harass Sakura in the Forest of Death, the newly cursed sealed Sasuke awoke from his tortured sleep and fought Zaku. Sasuke experienced his first taste of the Level 1 cursed seal power and quickly surprised Zaku. He grabbed Zaku from behind and severly injured his arms. Seeing that Sasuke was dangerous and that Orochimaru had used them, the Sound Genin quickly fled.

Zaku and his team did make it to the third round preliminaries, but he lost to Shino. Unfortunately for Zaku, Shino's destruction bugs fed on chakra, and managed to plug the air holes Zaku had in his arms. This caused the pressured air to be unable to escape, resulting in the destruction of his arms.

Later, when Orochimaru used his forbidden jutsu Edo Tensei, he needed a sacrificial body to hold the soul of one of the dead Hokage. Unfortunately for Zaku, Orochimaru used him one last time and sacrificed him to help complete the jutsu.

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When Naruto fought Sasuke at the Valley of the End, Zetsu spied on the proceedings. When Kakashi came to retrieve Naruto, he emerged from the ground and watched them return to Konoha. Several years later he watched over Guy and his team who were going to meet up with Kakashi in their search for Akatsuki. He was later commanded at one time to eat the bodies of Sasori's dead subordinates.

Zetsu later appeared in the destroyed former cave base of the group with new recruit Tobi. One of Zetsu's sides favored Tobi and thought of him as a good young man. When Tobi found Sasori's ring, Zetsu debated whether the young man was worthy to replace the former member. Later when Hidan and Kakuzu captured the Nibi Jinchuuriki Ni'i Yugito, Zetsu arrived to take on the duty of returning her body to their base of operations. After several of the Akatsuki members fell in battle, the remaining survivors were Tobi and Zetsu. Though Tobi portrayed himself as being Uchiha Madara, it was revealed he was Uchiha Obito. White Zetsu had history with Obito, having helped the boy recover after falling in battle. It was then revealed that White Zetsu was made by Uchiha Madara from the genetic material of Senju Hashirama amplified by the power of the Gedou Mazou statue. White Zetsu was then cloned through buds from the Gedou Mazou root system. One of these clones combined with Obito when he learned that his former teammates Rin and Kakashi was in trouble. Upon seeing Rin being killed by Kakashi, Obito lost control. Through being combined with the Senju power, Obito awakened his own full abilities. When Obito decided to help Madara carry out his plans, Madara formed his dark chakra-like "will" into the being which would become the Black Zetsu half. The now full Zetsu would assist Obito as he carried out his duties in the guise of "Madara".

Years later, the two men would carry out the Fourth Great Ninja War with the help of Yakushi Kabuto. His assistance allowed for the creation of thousands of White Zetsu clones. These clones could communicate over short distances telepathically and served as the main bulk of the Akatsuki forces. The original White Zetsu was left behind to watch over Sasuke, who had received his brother's eyes. Upon recovery, Sasuke tested out his new powers by killing the original White Zetsu. Black Zetsu was later neutralized in battle by Choujuurou.

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Gatô ordered the partners Waraji and Zouri to grab Tazuna's daughter as a hostage. They were about to succeed but Naruto showed up and quickly defeated both of them.