This all depends on the game environment. Take minions in Feng Shui. The rules there are, in short, that all minions die if you hit them for more than 5 damage, but a hit for less than 5 damage is not tracked. So you can hit them indefinitely at 4 damage per hit, but only once for 5+. This works for Feng Shui because most characters hit for way more than 5 damage, so the realism breakage that would occur if you smacked a minion 12 times for 4 damage each (enough to kill a major named character) is very unlikely to happen.
Regarding these minion rules, if level 21 characters are regularly throwing around 1 damage attacks, then minions won't work so well. But if level 21 characters rarely or never throw 1 damage attacks, then everything is fine. As long as the typical attack damage is high enough that is plausible that it would kill a minion, there isn't a problem.
So... let me think about what's in the game.
Basic attacking follows a 1[W]+Stat progression, with a boost at epic level. I don't think there will be a problem there, except possibly if you end up with a wizard knifing a level 26 minion with a nonmagical dagger or something. But since wizards have at will magic that does way more damage than their crappy dagger powered by a strength score of 8, I don't think this will be a noticeable problem.
Area of effect powers don't look to be a problem, because they tend to do significant damage. At will area of effects like Scorching Burst already don't do any damage on a miss. Same with Burning Hands. Its only daily powers like Acid Arrow that do half damage on a miss, at least so far. This could bug people, but I doubt it will come up often, since Wizards have better options for killing weak foes. If it does come up, I'll DM around it. If a Wizard wants to use a daily power to waste one minion, I may just let it happen. Why not?
Attacks that do only [Ability Score damage] could be an issue, but I don't think they will based on what I know at the moment. This would be stuff like Cleave or Reaping Strike. This is probably the most dangerous territory, because at least hypothetically someone could take Cleave and then never increase their strength score above a +2 or something. But that would be moronic for a Fighter, so I'm figuring it won't happen. At level 21, I expect most Fighters will have strength bonuses of around +6 or more, due to the rate at which ability scores increase. Reaping Strike is a little tougher, since letting minions die to it violates the "minions don't die on a miss" rule. This puts us in the Feng Shui Minion territory, where you can Reaping Strike a minion indefinitely for 4 damage, but only connect once for 5. I may adjust that slightly, so that if you miss a minion with Reaping Strike more than once or twice, it eventually dies. That will be an on-the-fly adjustment at most, though.
Combat involving vastly divergent power levels might be a concern, but probably won't. The secret to not having level 1 PCs beat up level 21 minions is to not have them meet. That works for me. If the PCs party involved several level 15 characters and a single level 3 character, that might create problems, but honestly that's already a problem. And if they have a low level NPC trailing along with them, well, I'll just ad lib the NPCs combat. I always did in the past for non combat relevant NPCs.
Low level items saved up until higher levels. Lets say that at level 1, you buy a flask of burning oil that does 1d8 damage. At level 30 you throw it at a bunch of minions, because you haven't used it yet and you never took it off your character sheet. It might bug me if PCs started doing this. Since the damage in this type of item is based on the item, not the character (at least in 3e, we don't know in 4e) its possible for level 30 PCs to bring level 1 guns to a level 30 fight. It would bug me if doing this to clear out minions became commonplace. That's about the biggest criticism I've got, though.
