When you spend an hour making code changes that have absolutely no effect and tearing stuff out to find out what is going wrong... Only to realize that you're serving a different file from the one you're working on.

Or that some other program alters file content while you're working on it...

Worst case I had was with Renesas HEW, an IDE for Renesas Microcontrollers. That thing has so many flaws and bugs, it's really annoying (should have replaced this thing with a few makefiles and some manually made build configurations, but now it's too late). One of the bugs is that if you have two projects within one workspace that have files with the same name, but in different directories, the IDE sometimes uses the file with the same name from the wrong project.
So a whole lot of errors, but you cannot find anything in the given file and no changes will ever have any effect.
I don't know when and why this happens, but every once in a while it appears and then disappears suddenly.