Many years ago, humans and demons lived in harmony. But that unity ended when demons started attacking humans and plotted a mission to unleash Gyumao—an evil demon imprisoned for thousands of years. Now, Genjo Sanzo, a rogue priest, must team up with three demons—Sha Gojyo, Son Goku, and Cho Hakkai—and embark on a perilous journey to the west to stop these demons from resurrecting Gyumao and restore the balance between humans and demons on Earth.

On a sunny July day in the 41st year of the Shinka Era, Jirou Hitoyoshi is tasked with covertly listening in on a secret meeting between a top government scientist and an industrial spy. However, his cover is blown, and the spy reveals himself to be an alien in disguise. Amidst the ensuing chaos, Jirou enlists the aid of cafe waitress and magical girl Kikko Hoshino, one of many "superhumans" who blend into society and secretly protect humanity from extraterrestrial threats. As a member of the government agency known as the Super Population Research Laboratory, Jirou has the dual task of protecting superhumans that defend humanity and disposing of any deemed too dangerous to live. Having proven herself a worthy ally, Kikko is invited to join the agency as its newest recruit. Fast forward five years: disapproval and distaste for superhumans are now commonplace in Tokyo. From government corruption and conflicting ideas of justice, to the morality of superhuman rights, the relationship between humans and the supernatural minority balances precariously in a world pervaded by whispers of unrest and unease. Under mysterious circumstances, Jirou has betrayed the agency, and is now a fugitive on the run. As he skulks through the rainy back alleys of Shinjuku, he is pursued by the very same superhumans that he himself once recruited.

Titans from outer space, life forms from a mystical world, phantoms and goblins from ancient times, cyborgs created by scientists, relics that rose out of the ruins of ancient civilizations. In another Japan, it's not just a question of "what if"—it's a reality. Some of the superhumans choose to keep their identities a secret, while others bask in their superhuman fame. Jiro Hitoyoshi, member of the Superhuman Bureau, keeps track of their doings.

Natsume Yuujinchou San follows Takashi Natsume, a boy who is able to see youkai. Natsume and his bodyguard Madara, nicknamed Nyanko-sensei, continue on their quest to release youkai from their contracts in the "Book of Friends." Natsume comes to terms with his ability to see youkai and stops thinking of it as a curse. As he spends more time with his human and youkai friends, he realizes how much he values them both and decides he doesn't have to choose between the spirit and human worlds to be happy.