Even though iTunes is my bailiwick over at Macworld, I've found the new Up Next feature to be quite confusing. It's taken me a while to suss out all its details and I've figured it out, but I find it quite confusing.
In updating my Take Control of iTunes: The FAQ ebook, my editor, Michael Cohen, noted a useful keyboard shortcut for working with Up Next. If you press Command-. (that's a period), this stops playback and clears the currently playing track from the iTunes LCD. I haven't yet found a way to clear the Up Next queue from the keyboard, however. If anyone's spotted a shortcut for that, feel free to post it in the comments or submit it as a hint. (As a reminder, you can display the Up Next queue by pressing Command-Option-U.)
Mac OS X Hints
http://hints.macworld.com/article.php?story=2012122600533091