For two monitors on one video card, things are pretty okay on Ubuntu and derivatives. More than that, especially 3+ with non-uniform geometries, and you will have fun. If you have multiple video cards, you will have even more fun.
Setup was pretty simple using the binary nVidia drivers on Kubuntu, 0 config file wrangling.
Now, having those three monitors in non-uniform geometries is something I wouldn't even consider tackling
[EDIT]
Kubuntu 12.04
All monitors in a single X Session and automatic application window sizing works as you would expect in KDE
(i.e. Maximising a window maximises to the current monitor only and being able to drag to right side of one monitor causes the window to use up half of the current monitor)