I use two screens.
I have them set up so there is a principle screen and a secondary screen as opposed to having one page spread over two screens, if that makes sense.
The advantages for me are I leave my email and sidebar ( I use Vista) on one screen so I can view them all the time whilst my main screen is whatever I want.
Usefully in this arrangement if you take an unmaxed window it can simply slide it over to the other screen if you wish to have it available whilst viewing another window say in full screen mode. In other words good for multi tasking or the convenience of one window not overlapping another.
The size difference will not matter all you need to do is set up the correct resolutions for each monitor.