You need extra functions in your window manager for moving between screens with multiple monitors. Depending on their placement the shortcuts might be non-intuitive. Different screen resolutions lead to unnatural movement of the mouse cursor between screens.
I've also found that such extra complexity impacts productivity negatively. It's an unnecessary distraction trying to communicate such complicated layouts.
I like to sum up this debate like this:
With multiple monitors, you're confined into smaller, "hard-coded" boxes that can't be changed. With a single large screen you have much more flexibility.