I think I've found an undesirable complication in highlighting when using multiple monitors; if the highlighting tool is resident in a window of a different monitor than the resource you want to highlight is in, then it can be a challenge to use highlighting unless you float the highlighting window or dock it in the monitor you want to work in.
For example, I have a book open in monitor #4 with some highlighting in it. I've got the highlighting tool open & docked in a window in monitor #3. If I drag my mouse over the text that I want to remove highlighting from, then select "Erase" from the highlighting menu, nothing happens. If I Crtl-K, then (usually) it will apply the last highlighting that I'd been using. If I select a different type of highlighting, it will apply that correctly, although there is a slight delay. I've tried various things to try to leave the focus of the resource that I want highlighted when I click on highlighting in the tool (docked in a different monitor), but that often doesn't work.
A big gotcha is that if I left something highlighted (i.e., i'd dragged my mouse over it) in a different monitor, it will be changed/too...for a while I couldn't figure out why my other resources were changing.
My workaround is to dock the highlighting tab in the monitor that I'm working in...and try to remember to not leave text "moused over" in windows of other monitors.
I am running 4.0a SR-3 on Vista64.