Assuming you are just going to hit someone with a sword. You will have a harder time trying to hit someone who has a sword in his hand than a person with empty hands. That's because he will force you to keep your distance and has a chance to parry your attacks!
What was missing in so many RPG systems so far is the ability of a weapon to parry and have some defense rating. I think it shouldn't be so hard to implement such a thing in a game. And its usefulness will surely shine in the cases mentioned below...
Engaging Multiple Enemies
Imagine you are back in the Baldur's Gate series, hacking away at multiple enemies. What do you usually do with your fighters? You order all your fighters to focus on one guy to bring him down quickly.
But thinking realistically this doesn't make sense. You should be facing someone who is trying to hit you!
Therefore, I propose that there should be some kind of a penalty when you don't attack an enemy who is attacking you but you prefer to hit someone else. This can be implemented as letting go of the sword defense bonuses which I have explained above and perhaps resulting in some additional defense penalties (due to combatant trying to fight multiple enemies) because you are not facing your enemies.
The extent how high these penalties might be is subjective, but it makes sense to make them cumulative. This would surely make it a real challange even for a single level 16 fighter to face 10 goblins at the same time.
This will also be an incentive for the players to use disabling spells, use summons, trying to lead the numerously superior enemy to choke points etc.
When you are trying to separate from your enemy and try to withdraw, it is highly risky that you turn your back and start running. Your enemy might score a hit of opportunity at the moment your back is turned to him. Therefore, it makes sense to implement a withdrawal mechanic in the game.
Basically, if your character is fighting an enemy and you order your character to fall back by the walk command, he does so by slowly falling back as he continues fighting. If you order him to run back, he turns his back to his enemy and starts running away. As soon as he turns his back to the enemy, his defense is lowered and his chance of getting stabbed is higher.