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.

Satoshi, Iris & Dent continue their travels through the Isshu region. After successfully winning his 8th Gym Badge against Homika in Tachiwaki City, Shirona invites everyone to stay at her villa in East Isshu, where old friend Hikari is also staying, and participate in the Pokemon World Tournament Junior Cup before Satoshi participates in the Unova League. Team Rocket, meanwhile, initiate their final plan for the Isshu region-what is their purpose in their desire for the legendary Pokémon Meloetta?

In this new series, Satoshi, Pikachu and friends start a new journey towards the "White Ruins." There, they meet the young "N", who can hear the voices from Pokémon's hearts... The door of truth leading to an Utopia for Pokémon and humans now lies open! (Source: AniDB)

In 1929, Ladd Russo spared Graham Specter's life and earned his unwavering loyalty. Three years later, Graham is infuriated upon learning that Ladd was pushed off the train after the events aboard the Flying Pussyfoot. As a man of bizarre yet passionate philosophies, he plans to make an offering to Ladd by kidnapping Eve Genoard and subsequently capturing Jacuzzi Splot, who has been living in the Genoard mansion with his gang. Meanwhile, Jacuzzi and his gang take in an unfamiliar woman, Elmer C. Albatross pays a visit to the prison to meet an old friend, and Czeslaw Meyer runs into the man he hoped he would never see again. These seemingly separate storylines merge, tying up several loose ends and revealing the whole truth of the anomaly that occurred aboard the Advena Avis in 1711. [Written by MAL Rewrite]