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Many years ago, humans and demons lived in harmony. But that unity ended when demons began attacking humans and plotted a mission to unleash Gyumao - an evil demon imprisoned for thousands of years.

Saiyuki is the story of four anti-hero-like heroes: the monk Genjyo Sanzo (or just "Sanzo"), the monkey king Son Goku, the half-demon Sha Gojyo, and the man who turned into a demon Cho Hakkai (formerly known as Cho Gonou). They have been dispatched by the Sanbutsushin (the Three Aspects of Buddha, who relay the orders of heaven) to travel to India to stop the possible resurrection of the Ox-Demon-King, Gyumaoh.

Priest Genjo Sanzo and companions Cho Hakkai, Sha Gojyo, and Son Goku maintain their westward journey to stop the resurrection of the demon Gyoumao. As the reputation of the Sanzo Ikkou precedes them, they continue to fight demon assassins at every turn, but they must also deal with increasing tensions within their group in order to defeat a powerful enemy.