Pokémon trainers Ash, Brock and Misty have traveled to the canal city of Altomare for some Pokémon related games. There, they learn about the legendary Pokémon protectors of the city, Latios and Latias, that haven't been seen in a long while, but are reportedly able to take human form as well as turn invisible.
They're not the only ones interested in them, however. Annie and Oakley are thieves working for the unseen Giovanni who have been sent to capture the elusive Pokémon as well as steal the Soul Dew. It's a gem containing the spirit of another Pokémon that also protects the city, but could be used as a powerful weapon should it fall into the wrong hands.
Ash and his friends then meet Bianca and her grandfather Lorenzo who are the only two humans who have regular contact with Latios and Latias. When Annie and Oakley kidnap those two Pokémon and steal the Soul Dew, it's up to Ash, his Pokémon, Pikachu, and the others to thwart their diabolical plan and save the Pokémon.