I've been contemplating these sorts of questions as well. Here are a few thoughts I've had.
The relatively little things:
Flatten Ability Scores: I mean two things by this. First, secondary stats could be less important. This would make more multiclassing options viable, instead of only those that overlap with a primary or secondary stat. Second, one could lower ability scores overall. There is a boring sameness in the number of two-18 1st level characters. Moreover, increases in abilities over levels create all sorts of math problems (masterwork armor, sagging NADs, etc.). So just scrap 'em.
Spaces: 1 yard/meter hexes.
Simplify the Math: Bake all the bonuses to attack, damage, and defense or core roles abilities into the shared or class progression. Magic items don't need to scale; a +1 (or +2) should remain relevant at all levels.
Essentials Warlord: I want one!
Feat Add Breadth, Not Depth: Feats shouldn't add bonuses unless they're designed to make a subpar build viable (e.g., quarterstaff users). I would like to see more feats that unlock new ('trained-only') uses for skills, and ones that increase non-combat effectiveness. Fewer feats might make sense too.
Utility Powers: Should almost always have non-combat uses. They're called utility powers.
The bigger/more controversial things (I expect):
Bring Back Exploration: Find a way to make traps, shorter fights, etc. really matter. Not just setpiece battles. Dungeon delves are boring in comparison to genuine dungeon crawls.
More Monster Immunities: Every power need not be useful in every fight, especially if fights are shorter.
Distinguish Power Sources: I really like that Essential martial characters don't have daily powers. What if every power source had a different structure for AEDU? Arcane characters might lack encounter powers and have more dailies. Primal characters might not have magical at-wills. The content of powers could also speak to power source (e.g., maybe warlords give temporary hp instead of healing or can only restore hp to characters that aren't bloodied, etc.).
Less At-Will Magic: I like the mixed power source classes that showed up later, with martial at-wills and magic-sauce encounters and/or dailies. I don't need a barbarian that's magical every round. Make more use of subclasses. An Avenger could be a Slayer that gives up some static bonuses for Daily Oath of Enmity powers. I don't need to swear a new Oath of Enmity multiple times every fight.
Fewer Powers per Character: Two dimensions to this. First, cutting down on the giant number of powers that each character has as they level up would speed up play and make encounters more varied (rather than a set checklist of powers for each character). Second, finding a way to eliminate the powers that are just higher level versions of other powers (e.g., hurricane vs. storm of blades) would help eliminate bloat.
Fewer Levels, More Tiers: I don't need 10 levels per tier. Give me 20 levels, made of 4 5-level tiers.