I've played in a few RPG sessions, mostly one-shots, involving giant rampaging monsters. They've been disappointing because they focus on killing the monster, which reduces this huge lumbering horror to litte more than a 40-story sack of hit points.
At the opposite extreme are monsters who can't be defeated (and I'll admit to unleashing one of these in my campaign; a CR 35 horror that destroyed the city of Stoneheim in the World of Greyhawk). Those can be equally disappointing for players because characters (especially high level ones) think they can defeat anything.
Then again, maybe that's missing the point.
Walking with Monsters
Consider Cloverfield, Matt Reeves and J.J. Abrams's ode to monster movies in which a gigantic, Godzilla-like creature attacks New York City. The movie shows that sometimes it's not about stopping the monster -- it's about surviving it. It's about escaping the creature's spawn and completing the individual side quests -- rescuing a lost love interest, saving a fallen brother, getting a friend to medical aid -- that create emotional tension even as the creature provides the physical threats.
Regardless of the system I'd likely stat out the monster in all its colossal, building-crushing glory, if only so I know how impossible it is to fight. Rather than just focus on giving it a bunch of hit points or wounds though, I'd look at specific traits that the monster or characters can use to their advantage. On the monster side, I'd want catastrophic attacks like a breath weapon that can incinerate tanks or a tail swipe that can knock down a building. In D&D 4E and Star Wars terms, I might define these as hazards -- things you can't hope to destroy, but you can avoid and perhaps negate (e.g. a Acrobatics check might provide a bonus to Reflex Defense to avoid being hit by debris).
Those who don't directly attack the creature the fallout in its wake: hazards created by crumbling buildings, skill challenges to navigate the ravaged city scape, firefights with individual monster spawn. The same goes for megamonsters -- say a rampaging titan or the infamous tarasque -- in any edition of Dungeons & Dragons
The No Win Scenario?
It's inevitable that our heroes would want to go toe to do with the creature, but even then it's not about not about killing the monster ... it's about defeating it.
It's unlikely that any given hero could take on the Cloverfield monster except in the most high tech SF campaign or high magic fantasy one could fight it toe to toe. The more likely approach is research missions to figure out how to fight it (perhaps through a skill challenge?) and strategic air and artillery strikes (with our heroes serving as advanced teams).
I'd want to build in some tools the players could use. Specific weaknesses that can be used to drive side quests -- e.g. an aversion to light or electricity) or notable vulnerabilities (e.g. Smaug's infamous missing scale in The Hobbit). Taking advantage of these tools may be difficult or even nigh near impossible ... but they should be there. It gives the full frontal a chance, even if it's a suicidal one.
That said, the final weapon might not that all-or-nothing heroic attack on the monster; it could come down to having to making the hard choice. In Cloverfield the ultimate solution to the monster problem is "Hammerdown" -- a nuclear strike on Manhattan.
I think it would make for an exceedingly cool adventure for players to spend 3 hours dealing with the monster and have the final hour be the culmination of their encounters. Will they try one final desperate attack on the monster? Will use information gleaned to try and lure it away from the city? Or will they evoke the nuclear option (whether its technological or magical) and devastate the city to save the country?