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- Pokémon have Natures, Abilities and Genders. Pokemon can hold items as well.
- The Pokémon are capable of Generation II and III evolutions, but cannot evolve into them without first obtaining the National Pokédex. An example would be Golbat evolving into Crobat.
- Certain Pokemon have changed their types. An example are Magnemite, who are now Electric/Steel type.
- Pokémon can now breed in the daycare on Four Island. Pokemon can still can go to the daycare on Route 5.
- Version-exclusive Pokémon and placement of wild Pokémon has been changed, due to new evolutions from Generations II and III.
- Legendary Pokémon have also changed. Articuno and Zapdos are still found at the Seafoam Islands and Power Plant respectively, but Moltres is now found on Mt. Ember, a volcano located in One Island, only accessible after defeating the 7th Gym on Cinnabar Island.
- Mewtwo remains in Cerulean Cave, but you can also obtain one of the Legendary Beasts as well. Entei, Raikou, or Suicune may be available after the Elite Four are defeated once. Only one of these can be obtained per game play, determined by the starter you chose at the beginning of the game. The Legendary Beast can only be found at random, in the tall grass in the Kanto Region.
- Lugia and Ho-Oh may also be caught if the player obtained the event item MysticTicket, and has defeated the Elite Four. Their locations can be accessed by going to the harbor with the ticket.
- The player can catch Deoxys if the event item Aurora Ticket has been obtained. Its location can be accessed by going to the harbor with the ticket. You will catch it in Attack Form in FireRed and Defense Form in LeafGreen.
- Movesets are updated and include the moves added in Generations II and III.
- The TM list for Fire Red and Leaf Green will be the Generation III list, not the Generation I list.
- Move Tutors are now available and can teach Pokémon the Generation I TMs. Blast Burn, Frenzy Plant, and Hydro Cannon are new moves available to your starter Pokemon only, and are available from a Move Tutor on Two Island.
- Trainers that are found in the world now can be re-challenged with the Vs. Seeker. Information on major characters in the game, such as Gym Leaders are stored in the Fame Checker.
- The Elite Four can now be re-challenged. After completing the Sapphire quest at the Sevii Islands, The Elite Four will have Generation II Pokémon in their roster, as well as Generation I Pokémon.
- Team Rocket has a new base on Five Island, making them the only villainous team that does anything after the Elite Four.