Planning a Xinerama setup is pretty straight forward. There as essentially three things you need to take into account, screen resolution, color depth, and screen layout.
It is possible to have each physical screen in your Xinerama setup to have a different resolution. There are some advantages to this, I was able to use an old monitor which only operates at 640x480, and a bigger 17" at 1280x1024 in my setup. I have also heard of web developers and graphics designed who use one big "preview" screen and flank it with one or two smaller screens. I think this is one of the great things about the Xinerama extensions.
There is one significant problem with using multiple screen reolutions. Current generation window managers assume the screen is rectangular and will assume this rectangle is equal in size to the heighth and width of your total desktop. If you have one monitor at 1600x1200 and another at 800x600, your window manager will assume your desktop is 2400x1200. This leaves a big area below the smaller screen which the window manager interprets as "Empty", many window managers will try to utilize this space for new windows. There are ways to configure your window manager to minimize this problem but is a nuisance. As window managers become Xinerama aware and this problem will go away quickly.
Unlike with screen resolotion, Xinerama limits your entire virtual screen to one color depth. If you were planning on pulling out a cheap video card for your second display you need to keep this in mind. If your old video card only supports 8 bit color you might get a bigger display but most newer programs look lousy in 256 colors.
Layout decisions are fairly simple, you just need to decide how you want to lay out your monitors. Most people will simply place their monitors in a row and view their desktop as one giant monitor. It is also possible to overlap displays, or place them in more complex layouts. Keep in mind though what I said above about window managers expecting rectangular displays.