Oh how I hate this answer, but it has just worked for me...
Symptoms: it works fine for weeks, then simply refuses to debug.
Solution: close Visual Studio, delete the contents of the Bin directory, reboot.
Irritatingly it required a full reboot to get it to start debugging; restarting Visual Studio + iisreset
wasn't enough.
More info: I sometimes find that IE's cache is the culprit (strange but true). Therefore close all instances of IE, start IE, clear the cache, close IE, then try debugging with Visual Studio again.