I much prefer Asp.net without web projects but setting it up on a new PC resulted in the dreaded "Unable to Start Debugging" message when I hit F5.
This MSDN article PRB: "Unable to Start Debugging" is NOT the problem in many cases.
It could also be that the site/virtual directory you are attempting to debug is using a different version of the framework than your app (eg. 1.0, 1.1 or 2.0) and requires you to run ASPNET_REGIIS.exe
Or it might be IIS authentication settings...
BUT for me, today, the problem was that my site (using 'Local', not 'Web Project' settings) did not have a web.config file. Simply adding a web.config file fixed the problem (all the above settings already being correct). A 'Web Project' would automatically have a web.config file included, but creating and converting a 'Class Library' to a website did not... Oops!