All about the screen.
There seems to be concern about eye fatigue when using the 3DS for an extended period of time. From my experience, I would think that my arms would be tired long before my eyes were.
Looking at the Nintendo 3DS promo videos, you'll notice that all the models are holding the console in exactly the same position and exactly the same distance away. That's because there is only one angle to hold the 3DS at in order to see the 3D effects properly. Succeed with this, and you will have the sharpest of images. Avert your eyes even slightly, and things start to float where they should not, layers separate, things double up, and you lose the perfectly crisp image. Looking at the screen like that even for a short while is uncomfortable, but it is quite easy to slip into such a view.
3D images are really, really sharp, in part thanks to the 3D making round things look more spherical. This is the part that people are saying you can't appreciate until you see it. When it's done well, it enhances the character models, rather than just adding a layered effect with background and foreground components. The inside of the Deku Tree looks curved and smooth. It's a subtle enhancement, and that's the difference.
Turning off the 3D, you lose the life-like quality and crisp, razor sharp, yet smoothly joined edges, but the viewing angle increases accordingly.
While I didn't see anyone else do this, because of the strict viewing angle, I had to adjust the way I held the console to play Kid Icarus: Uprising. Your left hand controls the Circle Pad and L-trigger, as well as holding the DS. Most of the time, you can just hold down the trigger and that's fine, but if you want to charge or stop shooting, you have to take your finger off the button. In your right hand, you hold the stylus pen-style, so you're meant to hold the 3DS with your left hand supporting the console completely. I couldn't keep it balanced while having to press L, so I hooked the last two fingers of my right hand under the system in order to keep it stable. Basically, I had to work around the exact issue that Sakurai previously suggested.