To figure out how best to use multiple monitors, figure out what you're doing with your applications, and where you're wasting time.
The whole point behind multiple monitors is, after all, to save time and make you more efficient. If all you do is type into a word processor all day, a 2nd monitor isn't going to help much. If you need to monitor output from 8 different programs simultaneously, then 4 or 8 monitors might make you much more productive.
So, what kind of things are a waste of time? I've identified two big ones for me:
- Context switches: going from one program to another.
- Locating and clicking on something
Figure out what programs you use, what the penalty is for a context switch, and how often you do it or how much more effective you could be with more pixels, and that will help you decide the "best" setup for you.
Get into the habit of setting up applications and layouts in the same place - this allows you to develop "muscle memory" for common. Even starting up applications (on windows) in the same order every time can help shave a few seconds off each context switch - no hunting for which task bar item you need to click if they're always in the same order. On a GUI that support multiple desktops, same thing - group applications the same way each time and you're get a little bit more efficient.
There are a couple of things to watch out for, however. Having more programs visible is not always better. Having email and IM onscreen and visible all the time can be distracting, and take away concentration from whatever task you're working on, so if you're looking at a 3rd or 4th screen just to have those available consider possibility that you may end up less productive. Also, having a lot of pixels means a lot of mousing - if you can't use keyboard shortcuts, you'll rely on the mouse a lot more, and that can lead to RSI problems.