The game takes place about 10 years before the events of R/G/B/Y/FR/LG.
There are only 80 discovered Pokemon at this time. (You can use the rest of the national Pokedex after you beat the Elite Four.)
Most of the Gym Leaders are different -- Except Blaine, Giovanni, and maybe Lt. Surge. Agatha, Bruno, and Lorelei are gym leaders.
Your choice of starters are: Electabuzz, Magmar, Pinsir. (Neither Electa nor Magmar can evolve until post game.)
Ash's dad is the current League Champion; he has a name like Crimson/Cool shade of Green*. He has a line like, "I hope my baby grows up to be as strong as you!"
The story involves Team Rocket doing stuff. You don't actually get to learn it's Giovanni in this game. Maybe fossil Pokemon ressurrection was just discovered and TR is going to try to make an army of Kabutops/Omastars.
If they wanted to, they could just use 3D models and not have extra Pokemon post game.
"What are you waiting for, Mr. Howel? Start talking into a fish!" -The Skipper (Early B & W episode of Gilligan's Island)