As with both the Advanced Generation and Diamond & Pearl series before it, the Best Wishes! series begins with only Satoshi, headed off to the Isshu region, located far away from Kanto, Johto, Houen, and Sinnoh, with his Pikachu. After he meets up with the new trainer and rival Shooty and the region's Professor Araragi, he gains traveling companions in Iris, a girl from a town known for its Dragon Pokémon, and Dent, Pokémon Connoisseur and the Grass Pokémon specialist of the three Sanyou City Gym Leaders.

Due to a mysterious disease, the genius Iria Akagami has been forced by her family to stay in a mansion on the isolated Wet Crow's Feather Island with only a handful of maids. To keep herself entertained, Iria invites a variety of fellow geniuses to stay as guests in her home, including computer savant Tomo Kunagisa and her unnamed assistant, skilled fortune-teller Maki Himena, famous artist Kanami Ibuki, academic scholar Akane Sonoyama, and renowned cook Yayoi Sashirono. These visits progress as normal until one of the guests is found gruesomely murdered in the night without a single clue as to the identity of the killer or a possible motive. Tensions rise between those on the island as the killer remains at large, and Tomo's assistant takes it upon himself to uncover the culprit's identity before the murderous events progress any further.

A world where it has been established that people routinely swing between slightly different parallel worlds... Koyomi Hidaka, who lives with his father following his parents' divorce, meets a girl named Shiori Satou at the research institute where his father works. They both have a little crush on each other, but everything changes when their parents remarry. Koyomi and Shiori, convinced that they will never be together, try to jump into another world where they won't be step-siblings... There's no meaning in a world without her.

Eli, Chihiro, and Miyako try to form a band but end up looking to Katsuragi for help. In the process they meet Kanon and become friends/ rivals. (Source: ANN)