Mushishi is set in an imaginary time between the Edo and Meiji periods, featuring some 19th-century technology but with Japan still as a "closed country." The story features ubiquitous creatures called Mushi that often display what appear as supernatural powers. It is implied that there are many more lifeforms more primitive than "normal" living things such as animals, plants, fungi and bacteria, and Mushi is the most primitive of all.

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