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For me it's when I dread going to work every morning and bring the stress home with me at night. I'm generally good at compartmentalizing, so when I'm unable to, I know something is seriously wrong. Once I hit that point, it's time for me to move on.
I worked in an organization where that meme was close to the reality. If our supervisor was traveling it was like a completely different mood in the office. It was kind of odd how one person's presence or absence could make such a dramatic difference.
My current workplace is pretty nice. However, my last employer was a nightmare. I loved it when the managers weren't around.