... of several factors. First, as has been mentioned, there is the time factor: Will you have time to chamber a round? If you factor in accessing the firearm, drawing it, racking it, and aiming it, it becomes a question of seconds rather than split seconds. The Tueller drill demonstrates that an attacker who is within 21 feet can reach you before you can draw and fire a handgun, and that's with a round chambered. How much more time do you want to add?
Then there's the potential for screwing up and short-stroking the slide of your pistol because you're all sweaty and panicky, and thereby failing to chamber a round. Bingo -- instead of ready-to-use firearm in your hand, you've got a paperweight.
Finally, there's the concept of treating every firearm as if it were loaded. That's a fundamental rule, but would you still do this if you knew there was no round in the chamber? If you would -- i.e. not pointing it carelessly, not putting your finger on the trigger unless you're on an active range, not allowing anyone else to have access to it, etc. -- then you're not gaining any safety by not having a round chambered. If you wouldn't, then this pistol that you were careless with because you thought there was no round in the chamber becomes an accident looking for a time and place to happen.
Then there are the various legal complexities surrounding armed self defense. If you carry a pistol that needs to be racked before you can fire it, there will be a strong temptation to "make it ready" if you think you're in a potentially threatening situation. This is bad from a practical safety standpoint, in that you shouldn't be screwing around with your pistol in a public place, and from a legal standpoint, in that many jurisdictions would consider this "brandishing" as opposed to legitimate self defense.
All the training I've had says that the most important thing is to know your pistol and how to operate it safely. This is action-specific, to a large extent. Is it a single-action-only semi-auto? Then carry it cocked-and-locked: round chambered, hammer back, thumb safety on. This is the way SAO pistols were designed to be used. Is it a DA/SA semi-auto? Carry it hammer-down, with or without a thumb safety, which many consider redundant given the long and heavy trigger pull in double action. Is is a double-action-only semi-auto? Round chambered, hammer down. Striker-fired? Make sure that nothing enters the trigger guard when reholstering. And always follow the Four Rules.
As for revolvers, the only reason to carry with an empty chamber under the hammer was for drop safety in older revolvers. It won't prevent inadvertent firing, because cocking the hammer, whether in single or double action, will advance the cylinder, and you will then have a live round under the hammer. In any case, all modern revolvers have hammer-block safeties, rendering the "empty chamber under the hammer" scenario unnecessary: all it does is make your six-shooter into a five-shooter.
The overwhelming majority of carriers that I have encountered carry with a round chambered. That is not the cause of these tragedies. The cause of these tragedies is careless stupidity. Think your child is too weak or doesn't know how to rack a slide? Think your child can't figure out how to spin the revolver's cylinder? Think your child can't pull the trigger on a double-action revolver? Are you willing to bet your child's life on it?
A gun with a round in the chamber is safe if handled safely. A gun with no round in the chamber is not safe if handled unsafely.
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