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Asa and Kame strike up an immediate friendship when they arrive at the same time for their first day of duty at the Ooku, the splendid pleasure palace housing the harem of Lord Tenshi. The two young women are there to join the many hundreds of other maidservants—men are barred from entering, with immediate beheading the price of trespassing. It soon becomes clear that behind the luxurious lifestyle and ritualized routines of the Ooku lie sinister schemes and cynical rivalries. Meanwhile, a mysterious wandering potion-peddler known only as the Medicine Seller subtly insinuates himself into the Ooku, just as an uncanny, otherworldly menace begins to reveal itself.

A calm village residing in the mountains comes under attack from a demon-possessed boar one day. Ashitaka, a young man and prince of the tribe, engages the creature in an attempt to save his village. During the battle, the boar bites him on the arm, leaving it blackened and cursed. Following his village's traditions, Ashitaka is exiled and becomes a wanderer, looking for a solution to the curse before it engulfs him. Iron Town is a fortress under the leadership of Lady Eboshi. Through the clearing of the surrounding forests, Iron Town produces large amounts of Ironsand, used for gunpowder and other machinery. However, because of the forests destruction, nearby animal clans seek revenge led by a human girl of the Wolf clan called San. When Ashitaka comes to Iron Town, he discovers the area consumed in battle. Horrified, he attempts to create peace and befriend the Wolf Clan. However, after the forest's eradication and the ongoing war between Human and Beast, will the Spirit of the Forest be forgiving and accept Ashitaka's request to expel his curse?

The "Medicine Seller" is a deadly and mysterious master of the occult who travels across feudal Japan in search of malevolent spirits called "mononoke" to slay. When he locates one of these spirits, he cannot simply kill it; he must first learn its Form, its Truth, and its Reason in order to wield the mighty Exorcism Sword and fight against it. He must begin his strange exorcisms with intense psychological analysis and careful investigative work—an extremely dangerous step, as he must first confront and learn about the mononoke before he even has the means to defeat it. The Medicine Seller's journey leads him to an old-fashioned inn where Shino, a pregnant woman, has finally found a place to rest. The owner has reluctantly placed her in the last vacant room; however, as she settles in, it quickly becomes clear that the room is infested by a lethal band of mononoke, the Zashiki Warashi. With his hunter's intuition, the Medicine Seller begins his investigation to discover the Form, the Truth, and the Reason before the Zashiki Warashi can kill again.

Second Season of Mononogatari

Tsukumogami—spirits or "marebito" can possess objects of considerable age and gain a physical form. Although he is part of the Saenome clan that is in charge of peacefully sending them back to their own world, Hyouma Kunato despises them because one took away what was very precious to him. In order to cure him of this loathing, Hyouma's grandfather sends him to live with Botan Nagatsuki, a girl who is the master of six "friendly" tsukumogami and lives with them as a family.