Error : "Unable to start debugging on the web server..." ASP.NET 4.0
There aren't many details here, but I was getting that same error while trying to Start Debugging on a web application project in Visual Studio 2010 that I'd just changed from 3.5 to 4.0.
This solved the problem for me from the command line:
cd %windir%\Microsoft.NET\Framework\v4.0.30319aspnet_regiis.exe -i
Just make sure to go into IIS Manager afterwards and double-check your application pools and such, since it's likely that this will reset some of your configuration.