This is one of the things that just seemed to work well for me from the first time I did it in Windows 98 when I set up four monitors on a single system. The guy was a day-trader. I'm currently running two monitors now, both flat-panel 19-in.
The only thing I would suggest is that you use monitors of the same size, although not required.
Be sure your video outputs match the available input on the monitor. There are cards that have two analog, cards with one analog and one digital and cards that have two digital outputs. You can do it with a single card that has dual outputs or you can use two cards.
Some main boards with on-board video will detect an add-in card and automatically disable the on-board video controller and there is no way to re-enable the on-board without removing the add-in card. On those, you simply cannot use the on-board video with an add-in card present in the system. Then there are some main boards that allow the use of the on-board and the add-in simultaneously.
I just happen to have had the lucky circumstance of a system falling into my lap a few months back with one on-board analog and one on-board digital.