Manji is an infamous swordsman in feudal Japan who is known as the "Hundred Man Killer," as he has killed one hundred innocent men. However, there is something far more frightening than his ominous reputation: the fact that he is immortal. This is the handiwork of eight-hundred-year-old nun Yaobikuni, who placed bloodworms capable of healing almost any wound in Manji's body. To atone for his crimes, Manji resolves to kill one thousand evil men. Yaobikuni agrees to this proposal, saying that if he succeeds, she will undo his curse of immortality. Soon after this promise, Manji meets Rin Asano, a 16-year-old girl who requests Manji's assistance in killing those who slaughtered her parents. Initially reluctant, Manji refuses Rin's desperate plea. However, owing to her evident lack of strength, Manji changes his mind and agrees to protect Rin for four years. With this partnership set in stone, the two embark on a perilous journey of bloodshed, vengeance, and redemption, each to fulfill their own life's cause.

In the beginning, God created the heavens and the earth. He also sought after a wide variety of animals to populate the planet. However, he felt that it was too tiresome to think of new ideas within his criteria. To address this problem, God appointed an organization—the Heaven's Design Team—to do the work instead! Shimoda is a newly-hired angel who serves as the mediator between God and the design team. As he steps into his role, he witnesses his coworkers conceive interesting ideas for many unique life forms according to God's desires. From giraffes and snakes to birds, anteaters, and everything in between, the possibilities for different animal species are endless!

The entire countryside comes to a halt midday to witness a rare solar eclipse that is rumored to allow the average person to see Mushi. Unable to avert their gaze, the air is full of awe and wonder—but those who know the Mushi are preparing for the eclipse's aftermath. Based on a prediction from Tanyuu Karibusa, the cursed recorder, Mushishi Ginko finds himself in a very unlucky farming village. Immediately following the solar eclipse, a strange black cloud begins to gather in the sky and blocks the sun once more. Suspecting it to be the work of a Mushi known as Hihami, Ginko seeks to liberate the village from perpetual darkness. However, it seems that not all of the villagers are eager to return to the light.

Friends will only let you down—that is the sad truth Mei Tachibana lives with, ever since she was wrongfully blamed for the death of a class pet by her so-called friends in grade school. Since then, she stays away from people in order to avoid ever being hurt again. However, Mei's life begins to change drastically when a misunderstanding in high school causes her to encounter popular student Yamato Kurosawa. Yamato finds her intriguing and insists on being her friend, even though Mei wants nothing to do with him. But when a dangerous situation ends with Yamato kissing Mei to save her from the unwanted attention of a stalker, Mei begins to develop feelings for him. On the heels of her discovery that their feelings are mutual, they start dating and she gains not only a boyfriend, but friends as well. Mei, however, finds it very hard to adapt to this new lifestyle, especially in expressing her true feelings towards Yamato. Throughout misunderstandings of their new relationship, each other, and the attentions of other girls, Mei and Yamato slowly grow closer and learn the true meaning of those three little words: "I love you."