Hmm, I'm on level 40 and have barely touched the main quest. In fact, I'm not entirely sure what the main quest is. I think I'm supposed to do something for the greybeards, but it's not like I'll do it unless I'm in the area.
For the sake of challenge, I've only leveled my stamina, so my stats are 100 - ~500 - 100. That means I can sprint for an eternity, carry around a lot of shit and die from a single arrow! Still my biggest problem is storage..
I stick with expert and avoid fast-travel.
I don't think you can effectively gimp your character unless you deliberately plan to. No matter what skill you hone, you get your pick in health/stamina/mana on level-up. If you're using tank friendly skills, health is obviously your asset of choice. This might result in some tough battles, but the tougher they are the faster you'll progress - as you'll be dealing and taking a lot of hits. If you somehow get temporarely gimped you can always seek out trainers, hunt for skill books, probe for monies, etc. Plus, you actually get a good reason to use potions, scrolls and shouts.
I don't know, but magic wielding NPCs are probably the ones I fear the most in this game second only to bears. They can snipe you, kite you, violate your stats, summon shit, heal themselves; so if I'm not in a good sneaking position, I'll run the fuck away from adepts and higher.
My main gripes with this game so far are the menus, graphics and misc technical difficulities, and the number of voice actors. Only the latter is unfixable, but it helps that they're actually doing a good job. The only skill trees I miss are unarmed and unarmored. If you want to fight with your fists, you have to specialize in heavy armor - which doesn't make much sense. If you don't like armor, you can't be a traditional warrior what-so-ever. Getting rid of acrobatics was a good call; suddenly leveling up while jumping/sprinting/falling/swimming is stupid breaks immersion. The tech merges are otherwise very fortunate for playability - and has somehow improved character customization. The leveling system actually works in this game. I'll just say it - the gameplay is good. What Bethesda needs to work on is their NPCs/AI. Not just make shit work better, but give you more reason to care for them - a few more options in interraction wouldn't hurt either, as long as they stay clear of fucking mini-games. It's a miracle that there's no gimmicks in this game - unless you regard lockpicking as such.
I'll await judging it final after I'm completely done with the game. Like with Oblivion, it might be that I come to hate it after I'm done with it. Replayability is important to me, so if I end up hating it, I hate it - not matter what I felt while playing it.