In the spring of 1614, the retired shogun Tokugawa Ieyasu faces a succession dispute between his grandsons, Takechiyo and Kunichiyo. To settle the matter, he revives the ancient enmity between two rival ninja clans, the Kouga of Manjidani and the Iga of Tsubagakure, who have been at war for four centuries. The clans' no-hostilities treaty is nullified, and each must select ten elite ninja to fight to the death. A scroll bearing the names of all twenty combatants is given to each clan; the side that returns to Sunpu Castle with the scroll and the most survivors by the last day of May will see their chosen grandson declared the next shogun. By a random toss of the scrolls, the Kouga represent Kunichiyo and the Iga represent Takechiyo.

Both clans have been shaped by generations of selective breeding, which has granted their members extraordinary but often grotesque abilities. The Kouga are led by the elderly Danjou and his grandson Gennosuke, whose basilisk eyes turn any attacker's violence back upon themselves. Other Kouga fighters include the armless and legless prophet Jimushi Juubei, who spits a hidden spear; the spider-like Kazamachi Shougen, who weaves webs and shoots adhesive projectiles; the chameleon-like Kasumi Gyoubu, who merges with any surface; the rubber-bodied Udono Jousuke; the shapeshifting master of disguise Kisaragi Saemon; the blind night-seer Muroga Hyouma; the poisonous exhaling Kagerou, who loves Gennosuke; and the blood-draining Okoi.

The Iga are led by the matriarch Ogen and her granddaughter Oboro, whose occult-piercing eyes can nullify any ninja technique. Their ranks include the immortal and manipulative Yakushiji Tenzen; the whip-fighting Yashamaru; the limb-stretching Azuki Rousai; the whirlwind-creating Chikuma Koshirou; the hair-controlling Mino Nenki; the insect-summoning Hotarubi; the blood-misting Akeginu; and the liquid-bodied Amayo Jingorou, who dissolves into a corrosive slime.

At the heart of the tragedy is the love between Gennosuke and Oboro, the heirs of their respective clans. They had been betrothed with the hope of ending the centuries of bloodshed and reversing the genetic damage wrought by inbreeding. Now, forced into a conflict neither wants, they must choose between their feelings and their duty to their clans. As the ten Kouga and ten Iga ninja stalk each other through the mountains, forests, and villages of feudal Japan, the novel charts each duel and assassination, with the combatants using their bizarre and lethal ninja arts to eliminate one another one by one. The battlefield becomes a grim race to see who will be the last alive, and the star-crossed lovers are ultimately drawn toward a final confrontation that forces them to confront their love, their loyalty, and the cruel hand of fate.