At work I still have a fair number of clients who are focused on the various versions of the .NET Framework which leads me between VS 2003 all the way to VS 2010. Strangely enough I have spent the least time on VS 2008 which was actually a sizeable leap from 2005. Recently I have had a decent bit of exposure within VS 2008 and during a critical point of my testing cycle realized that my breakpoints were being either completely ignored or only being hit immediately after attaching the debugger. I tried all the normal checks on pdb file creation, which should not have been an issue during debugging, but I did not want to take anything for granted.
I finally found an article describing most of my issues on Microsoft support. It seems there is a need to install a patch to resolve this issue (KB957912). Which updates VS 2008 SP1 debugging and breakpoints. I was in a real pinch and this patched saved my skin!