There's a nice article on MSDN about some of the pitfalls and gotchas of debugging ASP.NET applications in VS.NET. If you've ever fired up the debugger and gotten an error, you should read this article.

I've only had one issue that I could never figure out what was going on, and rebooting worked. Those are frustrating. Of course, had I had this, it would have been much easier to find a solution.