A menace of huge monster-like insects is plaguing the land of Edo. Too powerful to be subdued by ordinary folks, the creatures are hunted by the Insect Magistrates—a group of warriors who specialize in various secret arts and combat styles. To bolster their strength, they summon Genjuurou Tsukishima, the master swordsman from the Tsugaru Province. Due to an unfortunate incident, however, Genjuurou is incapable of answering the call and sends his son, Jinbee, to serve in his stead. Determined to atone for the incident caused by his own cowardice, Jinbee agrees to travel to Edo and join the Insect Magistrates. Armed with his fiery spirit and unwavering resolve, Jinbee vows to become a stronger samurai and rid Edo of the insect threat once and for all.

Ghostly, primordial beings known as Mushi continue to cause mysterious changes in the lives of humans. The travelling Mushishi, Ginko, persists in trying to set right the strange and unsettling situations he encounters. Time loops, living shadows, and telepathy are among the overt effects of interference from Mushi, but more subtle symptoms that take years to be noticed also rouse Ginko's concern as he passes from village to village. Through circumstance, Ginko has become an arbiter, determining which Mushi are blessings and which are curses. But the lines that he seeks to draw are subjective. Some of his patients would rather exercise their new powers until they are utterly consumed by them; others desperately strive to rid themselves of afflictions which are in fact protecting their lives from devastation. Those who cross paths with Mushi must learn to accept seemingly impossible consequences for their actions, and heal wounds they did not know they had. Otherwise, they risk meeting with fates beyond their comprehension.

Mushi-uta's story takes place in the near future. Ten years before the story's opening, strange insect-like creatures known as Mushi began appearing. The Mushi are able to consume peoples' dreams and thoughts in return for supernatural powers. At the end of episode one, protagonist Daisuke Kakkou Kusuriya encounters a young girl named Shiika Anmoto. The two, in time, become quite close. However, unbeknownst to Kakkou, Shiika is an escapee from a secret prison known as GARDEN where those posessed by the Mushi, known as the Mushitsuki are held. GARDEN's military force, the Special Environmental Conservation Executive Office, dispatches its finest killer to track down Shiika. However, they are faced with resistance from the Mushibane resistance organisation, led by the secretive Ladybird. (Source: ANN)

Mushi: the most basic forms of life in the world. They exist without any goals or purposes aside from simply being. They are beyond the shackles of the words good and evil. Mushi can exist in countless forms and are capable of mimicking things from the natural world such as plants, diseases, and even phenomena like rainbows. This is, however, just a vague definition of these entities that inhabit the vibrant world of Mushishi, as to even call them a form of life would be an oversimplification. Detailed information on Mushi is scarce because the majority of humans are unaware of their existence. So what are Mushi and why do they exist? This is the question that a Mushishi, Ginko, ponders constantly. Mushishi are those who research Mushi in hopes of understanding their place in the world's hierarchy of life. Ginko chases rumors of occurrences that could be tied to Mushi, all for the sake of finding an answer. It could, after all, lead to the meaning of life itself.