ExploderWizard
Hero
On hitting enormous creatures without the right equipment (i.e. too low attack bonus).
Hitting in D&D represents not merely touching the target but also penetrating its armor and doing so with enough force to inflict actually relevant damage. Touching a large creature may be easier; penetrating it's thicker skin harder; hitting deeply enough to be more than a mere scratch: even harder.
The toughness of a creature is a combination of it's AC and HP. A big tough monster might have thick hide but it will also have lots of HP. A single pitiful attack against that kind of HP total is a mere scratch.
Are you going to do that for PC's and monsters? Doing so will dramatically change the game, which may be OK but don't expect normal balance assumptions to hold. PC's that trade higher defenses for lower damage (swordmage, paladin) will lose out relative to those that trade defenses for more damage (barbarian). THP and resistance rather than defenses will be much more attractive (barbarian, battlerager). Marking won't matter much unless there's a rider. Cover, concealment even total concealment become much less relevant unless there's some combination of factors. Power attack gets a lot better. And so on... Actually, if you want major balance changes, I think you should consider just switching to a different system since one of 4e's main strengths is its extremely robust balance: ask yourself what 4e brings to table if you take that away (not that there aren't other advantages, but I'm not so sure they're enough). 3.5 for example already took that path; merely hitting isn't usually a problem (except for those with many iterative attacks), the problem is dealing enough damage and status effects.
I plan on leaving my current campaign as is. These ideas are for my own project. Some 4E concepts will be a part of it but not the whole.