I think I've DM'd lots of major games out there at this point, and some not so major, including DnD 2nd and 3rd, Space Master, TORG, Cyberpunk, Darksword Adventures, etc, and played in many more.
I've been chatting with some friends in my WoW guild (European zone) off and on about doing some online play via TS and using Fantasy Grounds as the virtual surface. I've fiddled a bunch around with the demo and was really impressed. If you couple that with a good cartography program and various other tools, you can very easily set up a pretty good game with it.
I've been planning on buying it, so long as I can get the others to invest in at least the client part, which should be possible. And find the time of course.
I think a regular group like that could be fun. I haven't made the move to 4th edition DnD yet, but I have most things core and Forgotten Realms for 3rd edition.
I have, however, found that how fun a game is has a lot more to do with your players than it does with the system. If you have a good group of players who focus on thinking out of the box, you'll not only have more fun sessions, but you'll also be much more challenged as a DM, having to think on your feet and try to keep the game moving. It's not a good RP session without a little tension.