I think most people would be happy if the story and gameplay structure was messed around with. People are sick of the feelgood story of a young boy from a small town overcoming a group who use Pokemon for evil while simultaniously beating the best trainers in the world and becoming the best. Departing from that would make a huge difference in itself.
I also agree with skip/KylieDog and whoever else said that we need a return to basics. I love how the EV/IV/Nature/Egg/Held Item aspects of the game adds depth, but like others have said, it feels terrible to work really hard to train your Pokemon as good as you can, only to lose to to some hacker with a perfectly trained Pokemon. I think Natures are great, but maybe EV/IV should be trashed in favour of a new system that can make an individual Pokemon capable of having an extensive amount of strategic variations while still considered usable in serious matches. What I'm trying to say is that we should have much more freedom to mould each individual Pokemon into something that is original, and not just "X amount for attack, y amount for speed, and the rest in sp. defence!)
Balancing is also a big issue, but with the sheer amount of Pokemon created, it seems very unlikely. Also, I agree with the idea that there are too many Legendary Pokemon. I think that these Pokemon should stay exclusive to their respective games.
