I too fear that the instant gratification crowd has forever changed (meaning, ruined) Bethesda's approach to story-telling. Not that they've ever been masters of that craft, but without the massive success of Oblivion, I do believe they would've been motivated to go deeper, rather than bigger, when it comes to their Main Quests. They would've improved, or at least had an opportunity to.
Here's what I would be okay with in terms of a Main Quest for any number of possible game settings for TES VI...
Black Marsh: The various tribes aren't getting along very well at the moment (would be nothing knew to the region, I'm sure), and for unknown reasons that may or may not be related, the Hist are behaving strangely (something that is new). There's no civil war about to erupt or anything, but the tension combined with unexpected actions taken by the Hist, and possibly some other tree race we're not aware of, and possibly one of the tribes that seems to be gaining in power with no discernible cause, is making for a situation that could be easily exploited by an outsider looking to stir up trouble, or change the way things work in Black Marsh for many years to come. Basically, I'd like to see the player become a force to be reckoned with if they so choose, rather than be born special. I'd also like to see some facilitation within the overall story for the presence of foreigners in such an inhospitable province, some explanation that isn't as simple as "the Argonians decided to open the place up more because it would be good for trade" or some crap like that. The Hist could potentially help out with that in a number of ways, I'm sure. Any MQ in Black Marsh is going to involve them anyway. The player's character simply being someone who ended up in Black Marsh for whatever reason the player can come up with would be well in line with ES tradition, I suppose, but I think Bethesda can do better than that. Maybe the player was to be punished for committing some crime by being dumped in the middle of a swamp? That would work for me.
Summerset Isle: The hierarchy of the Aldmeri Dominion is prepared to make its biggest move yet against its biggest enemies (I don't know who this would be, but I'm guessing the Imperials to be the best candidate), and the player can either help it succeed (and position themselves to benefit from it greatly), or risk their life to stop the Thalmor from inflicting great harm to a great many people. Or something in between, like position themselves to benefit from efforts against Cyrodiil, but decide to delay the big plan in some manner in order to simultaneously save lives. I don't know, something to that effect. I like the idea of being able to be as involved as possible in the wicked machinations of the Altmers of Summerset Isle. They're so deliciously messed in the head.
Hammerfell: I don't know what to do here, actually. Something involving something left behind by the Dwemer probably.
High Rock: Don't want to go here, but if we do, I'd like an opportunity to get involved in what is sure to be conflict between the Bretons and the Thalmor. Orsinium rests within High Rock, and the Orcs getting involved would be nice too.
Valenwood/Elsweyr: The more I think of these two both being featured in the next game, the more I like the idea. Especially since the former is part of the Aldmeri Dominion, and the latter is unlikely to be happy about that. In RPGs, that can make for some real fun when you're free to visit either territory. Think of the possibilities in quests...
At best, what I really hope for is a story where I don't see future events coming a mile away. I want to be surprised, pleasantly surprised. I want to be challenged, and not just in terms of how many enemies I can take on at once. I don't mind the MQ being big, I just don't want to know how bad things are likely to get until I'm in deep enough that it's at least very difficult for me to turn my back and walk away, not because something will annoy me if I do, but because it just looks like there's too much fun I'd be throwing away. I don't want to know I'm destined for anything monumental right from the start. I just want to be involved in whatever interesting events are about to take place. If I end up saving the world, so be it. If I end up condemning it, then shame on me.