On a quiet and peaceful day, the skies split open and extradimensional beings, designated as the Unknown, launch a swift and brutal attack against humanity. To protect the future of the country, all of Japan's children are cryogenically frozen until the end of the war to keep them out of harm's way. Several years pass, and humanity has established a foothold in a corner of Japan, which now serves as the frontline of the war. No longer facing humanity's extinction, the children are awakened from their slumber. It is then discovered that, while in cryogenesis, the children had developed Worlds, supernatural powers unique to each person. The six most powerful children are given command of the reclaimed cities, using their powers to defend the strongholds against the continuing invasion. Childhood friends Ichiya Suzaku and Canaria Utara lead Tokyo, siblings Kasumi and Asuha Chigusa manage Chiba, and Maihime Tenkawa and Hotaru Rindou oversee Kanagawa. Over time, the almost routine attacks from the Unknown and the clashing personalities of the city heads and subheads cultivate petty rivalries, leading to constant arguments between the three cities. With the Unknown suddenly increasing the pressure of their attacks, the three cities' leaders must learn how to work together or risk losing the last line of defense against humanity's extinction.

A new era of exploration begins with the sudden appearance of a new continent known as Magmell. Magmell's vast trove of never-before-seen natural resources spurs on the exploration of its vast landscape. However, the unknown is not always docile. In order to sustain the expeditions, people known as anglers specialize in dealing with Magmell's dangerous wildlife. One such angler is the highly-skilled and experienced Inyou, who performs search and rescue operations for clients with the help of his assistant, Zero.

Living an abnormal existence in Ogikubo, an intergalactic melting pot of humans and aliens as well as the only Space Immigration Zone on Earth, Luluco is a bubbly middle school girl who just wants to be normal. One morning, however, her father, who works at the Space Patrol, eats a volatile sleep capsule by mistake and is frozen solid! To make matters worse, Luluco accidentally breaks him, so she hurries off to his office for help. There, the chief of the Space Patrol, Over Justice, hires Luluco as a space temp worker for undercover investigations, so that the institution may crack down on crime within her school. Made to don the Space Patrol suit and sent on her way to mete out justice, Luluco attempts to maintain the image of a normal girl who does not stand out in any way. But she soon discovers that with the automatic systems and inherently zealous judiciousness of the Space Patrol suit, continuing to be normal will be more difficult than she thought.

Shamans are extraordinary individuals with the ability to communicate with ghosts, spirits, and gods, which are invisible to ordinary people. The Shaman Fight—a prestigious tournament pitting shamans from all over the world against each other—is held every five hundred years, where the winner is crowned Shaman King. This title allows the current incumbent to call upon the Great Spirit and shape the world as they see fit. Finding himself late for class one night, Manta Oyamada, an ordinary middle school student, decides to take a shortcut through the local cemetery. Noticing him, a lone boy sitting on a gravestone invites Manta to stargaze with them. Realizing that them refers to the boy and his ghostly friends, Manta flees in terror. Later, the boy introduces himself as You Asakura, a Shaman-in-training, and demonstrates his powers by teaming up with the ghost of six-hundred-year-old samurai Amidamaru to save Manta from a group of thugs. You befriends Manta due to his ability to see spirits, and with the help of Amidamaru, they set out to accomplish You's goal of becoming the next Shaman King.