If you've ever used Microsoft Visio to mock up a GUI prototype, then you really need to check out the Pencil Project - it's a free add-on for Mozilla Firefox 3.
Using XULRunner, you can also run it independently of Firefox. This is well worth you taking a look. The layout and positioning of elements seems very slick - you won't be micro-managing the layout like you would in Visio.
[via Scott Hanselman's Ultimate Tools List]