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Tsunade was the fifth Hokage of Konohagakure. She is frequently referred to as "Princess" by older shinobi due to her connection to the previous Hokage: her grandfather, the First; her granduncle, the Second; and her teacher, the Third. During the Second Shinobi World War, she gained worldwide renown as one of the Legendary Sannin along with her teammates, Jiraiya and Orochimaru. Konoha's victory in that war is largely credited to Tsunade's achievements in medicine, which include the creation of medical-nin and their incorporation into shinobi squads, as per her own suggestion, which increased mission success and survival rates, forever altering the way they are carried out in not just her own village, but all across the world.

Furthermore, she was able to regularly counter the poisons created by Chiyo, an elite puppet master and poison specialist from Sunagakure, an enemy village during the conflict, which earned her Chiyo's everlasting hatred and a reputation as the greatest medical-nin in the globe. Also during that war, she became known as the Slug Princess of Konoha due to her tendency to summon slugs in battle, particularly Katsuyu, an enormous acid-spitting gastropod. Decades after that war, Tsunade is still hailed as the strongest and most beautiful woman in the world, and is thus a role model for young female ninja everywhere.

Through her grandparents, Mito Uzumaki and Hashirama Senju, Tsunade has biological ties to both the Uzumaki and the Senju clans.