My Wacom tablet does not save its screen mappings when I use two monitors.
It turns out the latest drivers: 6.37-3 for OS X or 6.37-6 for Window 7/8 have a bug, so when I configure the application mapping to a single screen when in Adobe Lightroom it forgets the settings when I next come to use it.
There is a work round, you can define a custom mapping range, if you make this range match the resolution of your monitor it basically does the same thing as a single monitor mapping. Only the custom setting is not forgotten.