The Lawful Indifferent blog has a post about treating out-of-scale monsters more as challenges than as combat opponents. The example is specifically a gargantuan monster, but really the concept applies to microscopic menaces as well, or environmental hazards. We don't normally run fights between PCs and earseekers, or calculate the armor class of a wildfire. The general rule should be "If it's not on the same scale as the PCs, it's not a fight."
As the reference to earseekers suggests, the concept has always existed in D&D. It's just that we haven't always been fully dedicated to running off-scale challenges without resorting to the combat rules. The canonical example are gods; there's been a lot of jokes made about Deities & Demigods or Gods, Demi-Gods and Heroes being monster manuals with bigger monsters. If you don't want players to fight Zeus, you don't give stats for Zeus; instead, when Zeus is involved in a situation, you get the equivalent of Phantasmal Forces (image of Zeus, in some form,) plus maybe a couple things the players can interact with.
For gargantuan menaces, you can, actually, set up a combat, for your combat-crazy players, but the "opponent" isn't really the monster in its entirety, but part of a monster, or a monster's action. A couple years ago, someone on RPGnet gave an example of a colossal sea serpent encircling a ship. My version of that answer is: figure that every five rounds, the serpent wraps another coil around the ship, and when the serpent has wrapped five coils around the ship, it will squeeze, completely destroying the ship in 2d6 turns. Each coil is a "monster" that the characters can attack; when the players "kill" one or more coils, different effects can occur:
- 1 coil: Subtract one from effective number of coils.
- 2 coils: Serpent rears head at bow or stern of ship (count as another "monster" that attacks anyone in that part of the ship.)
- 3 coils or head: Serpent uncoils and sinks back into the sea.
You can, similarly, set up a situation like Nick Wright describes, where there's some gigantic-ass beast destroying things and you can only kill it with heroic actions, not ordinary combat. What I'm getting at is that I would focus on the things described above for the sea serpent:
- What's it trying to do? (Destroy a city, destroy all cities, etc.)
- How long does it take to do it? (One per day, one per hour, one "step" per time period, as in the coils of the serpent example.)
- If there are multiple goals, how long between attacks? (Include a Move rate if it has to physically move to its next target, for example. If not, what's the downtime between attacks?)
- What can stop an attack? (Forget about killing it... just describe what series of actions will stop it, like "killing coils" of the serpent.)
- What happens after each action used to stop the attack? (See the list above for "killing coils".)
- What are the general effects of the monster's success? (What if the city is destroyed and the PCs are in it?)