How do you know when a guy is lying to you?

Eyes are the best indicators, when every other tested technique fails :-)

Honestly, there is no real way to tell. There are certain tendencies that the other answers mention that are general indicators of a lie, but not definitively. Sometimes people look in certain directions, slouch, or stutter naturally. Likewise, someone who is good at lying can avoid tipping it off by body language. It all comes down to common sense, in my opinion. If his story doesn't add up, or if he's being overly evasive, those are the strongest signs of a lie.

Do some research on body language- there are lots of ways to tell when someone (guy or girl) is lying, even down to the direction their eyes go when they are trying to think of a response (either making up something or trying to remember the truth).

When he opens his mouth, lol j/k. It depends on what you're referring to. If they pause a lot, or stutter, as if they're trying to think of what to say. If they're constantly looking up or down, and not looking you in the eyes. These are a couple signs that they could possibly be lying.