My main monitor is 24 inches and I have a 19 inch immediately alongside it, with an angle between them so I can look from one to the other and be normal to both. I don't do it very often, but occasionally I'll have both on at once.
I've found it useful for the following situations:
Working with non-intuitive software I often display help on screen 2 and work through the examples on 1 without having to keep juggling for visual access .

Detailed Spreadsheets or Documents - display 2 or more pages at once without bunching up on one screen and having to juggle.

You might want to have different views of the same thing in a Video Editor or keep flipping from Track to Piano roll and other views in say Sonar. Put them on different screens and leave them there all the time.
Similarly when running games if you're a fanatic (I'm not). For example Flight Simulator simultaneous ahead and left or right views.

Once the screens are configured all you do is create the windows you want on screen 1 and mouse-drag them to screen 2. You do have to have a grahics card with 2 screen capability.

I've never considered knowing which screen to look at could be a problem. Using static programs I find you just look wherever the work is being done.
The closer you get to the screens the more degrees you have to turn your head to look from one to the other. A swivel chair might help. It's easy with my distance of 20-25 inches
If you can look in the right places OK while driving a car I can't see that having 2 monitors creates an issue.

Unless of course screen 2 gets a mind of its own and starts displaying distracting images

John