What's the quickest and most reliable way to untarget your current target in GW2?

Left-clicking on the ground is the most reliable way to deselect all targets.

ESC deselects any selected targets, but if nothing is selected you will bring up your menu (can be annoying mid-combat).

There is also a key binding to target the nearest ally, which will select yourself if no other allies are around. This is useful if you are having trouble finding a patch of ground to click on. This key is not assigned by default, so look for "Nearest Ally" under Targeting in Options->Controls.

You can also select the next closest target using TAB, in case you do actually want to direct your spells towards a different enemy then the one you current have selected. Then again, a left-click on the target works more reliably if multiple targets are in view.

There is also a Guild Wars 2 printable keyboard layout to help you visualize the default key bindings.

You can click on the ground to deselect your target.

Most, if not all MMOs I've played allow you to deselect your target with the ESC key. I seem to recall Guild Wars 1 doing this as well. Likely the same here.

Click on any bare part of the ground to deselect.

Edit: It was later added that the Esc key will close windows, deselect, and stop actions by default (one per click). Esc will bring up the menu if no windows are open, no target is selected, and your character is not auto-running or auto-attacking.

As of the latest build, the quickest and most direct way to unselect a target is to bind the Lock Autotarget to an easily accessible key on your keyboard.

Despite what the tooltip might suggest, tapping the assigned key will untarget anything you are currently targeting.