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I have been working with 2 monitors for years.
This week I upgraded to 3 and after tomorrow will be using 4 (when I pick up a long enough DVI cable to reach)

Already with 3 I have found some productivity gains.
I have 2 22" widescreens as my main monitors and 2 19" widescreens either side of them. As my desk is a curved reception desk (curves through 90 degrees) they sit very nicely on it.
So how did I make it work? Well two BFGTech 8800GTX OC 768Mb video cards (SLI) help - and a massive server case fan to cool them!
I have the 2 19"s either side of the main 22" monitors. So from left to right they are numbers 3, 1, 2, 4
I am not 100% sure how I will utilise the 4th monitor yet, but it will mostly be used for not often used windows that I want to be able to see but not have to interact with much. (update - moved the Media player, MSN Window and chat screens to the 4th monitor and kept OneNote on monitor one)
On screen 1 I have Outlook, Dreamweaver, Excel and any current MSN chat windows. I also have One Note in the background - using it for screenshots and documentation notes - I plan to move this to the 4th monitor after tomorrow.
On screen 2 I have Firefox running about 20 odd tabs, about 8 or 10 I am actively using, and the rest are reference or checking things - eg Facebook, google rss reader, my bank account, some websites I have to check occasionally etc. I also have my main Windows explorer window here in the background. My gadget sidebar is docked to the right of that screen. The Gadget sidebar by the way has Outlook Mini status showing emails, calendar and tasks, a whats playing now box for the music, a currency converter so i can check what i owe my over seas developers in AUD, the weather, a 5 way time clock containing all my developers locations times a hard drive tool showing free space across 6 important drives across my network, a CPU (all 4 cores) and RAM utilisation gadget and a network traffic utilisation tool.
On screen 3 (to my left) I have MSN window of contacts, CuteFTP, Internet Explorer with a couple of tabs open - mostly anonymous views into websites, and medial player showing a play list from behind other the windows.
I plan to push MSN contact list and Media Player to the 4th screen along with one note. Maybe I will push IE there as well.
The other main applications I use regularly are Word (screen 2), Remote server connection to my SBS server (screen 3), Virtual PC for running Office 2003 applications (screen2), Quickbooks (screen 1) and 1 or 2 more windows explorer windows - usually temporarily opened for copying or something (usually on screen 1).
So what monitor setup do you use? - what works for you?