- You cannot really lock yourself out of anything.
- A possible exception is one of the main quests, "The Elusive Crane". When Dutchess asks you to wake up Crane, make sure not to accidentally kill him, or you won't get the keycard for the Gauley Mine Rob-co entrance. (believe this has been fixed via patches?)
- Pistols are not really supported as a realistic option beyond the early game due to a lack of empowering abilities.
- Similarly, melee weapons are limited Skyrim-style by having one of the major endgame events revolving around having to fight a flying dragon...except there's no shout to force it to land, so generally the group you're in will either slaughter it or be slaughtered by it long before it comes within poking distance.
- Shotguns are generally OP. Ammo is plentiful and there are perks to greatly improve their two weaknesses of spread/accuracy & reload speed, on top of the generic "do more damage" and "make this weigh less" perks.