Hey pals!
As someone who uses multiple monitors and plays in Windowed Fullscreen (Maximized Window) ; I can hold down an ability, i.e. Smite (which requires a target), and drag my mouse across multiple monitors, left, right, or up) to hit enemies that would be multiple screens away. The skill will not activate until it finds an enemy, so carefully dragging across multiple monitors allows me to find enemies before they could ever attack. This essentially allows me to clear a quarter of a zone without risk.