While I’m still a huge fan of paper prototyping there are two CSS frameworks that make rapid real world prototypes of web interfaces less painful. Blueprint and Yahoo’s Grids are both top-notch, cross-browser, and well documented libraries that you can use freely in your own prototypes. Certainty they can be used in production as well, but that’s another posting - what I’m talking about is being able to bang out a basic wireframe design that has all of your core elements in more or less the right place. You can do this rapidly in either framework and it won’t take you more than an hour or two. (I can can whip up a Blueprint shell in under twenty minutes for a variety of common layout concepts.)
Right now I’d say Blueprint has a clear edge over Grids, but the YUI team has been quick to adept to new ideas so it is worth keeping an eye on their blog. It is also worth noting that Grids doesn’t require the JavaScript components of YUI - a common misconception.