I have run into this issue numerous times, but from time to time I keep forgetting what causes this issue.

The symptom is that your breakpoints inside Silverlight application cannot be hit, and the information message states that “No symbols have been loaded for this document.”  What is usually strange that I was able to debug just a little while ago.

The most common cause is that Silverlight debugging is not turned on on web site project that hosts Silverlight application.  However, I have not run into this issue.  My number one problem is that ClientBin folder stops being updated.  This can be caused by the fact that somehow the folder is checked into source control and compiler cannot overwrite the XAP file any longer.  Or, file is being held by OS, maybe because Visual Studio crashed at some point before.  To troubleshoot, just check your XAP from ClientBin folder and check source controls.