Doing the night shift throws the body "into chaos" and could cause long-term damage, warn researchers.
Shift work has been linked to higher rates of type 2 diabetes, heart attacks and cancer.
Now scientists at the Sleep Research Centre in Surrey have uncovered the disruption shift work causes at the deepest molecular level.
Experts said the scale, speed and severity of damage caused by being awake at night was a surprise.
The human body has its own natural rhythm or body clock tuned to sleep at night and be active during the day.
It has profound effects on the body, altering everything from hormones and body temperature to athletic ability, mood and brain function.
The study, published in Proceedings of the National Academy of Sciences, followed 22 people as their body was shifted from a normal pattern to that of a night-shift worker.
Blood tests showed that normally 6% of genes - the instructions contained in DNA - were precisely timed to be more or less active at specific times of the day.
Once the volunteers were working through the night, that genetic fine-tuning was lost.
"Over 97% of rhythmic genes become out of sync with mistimed sleep and this really explains why we feel so bad during jet lag, or if we have to work irregular shifts," said Dr Simon Archer, one of the researchers at the University of Surrey.
Fellow researcher Prof Derk-Jan Dijk said every tissue in the body had its own daily rhythm, but with shifts that was lost with the heart running to a different time to the kidneys running to a different time to the brain.
He told the BBC: "It's chrono-chaos. It's like living in a house. There's a clock in every room in the house and in all of those rooms those clocks are now disrupted, which of course leads to chaos in the household."
Studies have shown that shift workers getting too little sleep at the wrong time of day may be increasing their risk of type-2 diabetes and obesity.
Others analyses suggest heart attacks are more common in night workers.
Prof Dijk added: "We of course know that shift work and jet lag is associated with negative side effects and health consequences.
"They show up after several years of shift work. We believe these changes in rhythmic patterns of gene expression are likely to be related to some of those long-term health consequences."
Prof Hugh Piggins, a body-clock researcher from the University of Manchester, told the BBC: "The study indicated that the acute effects are quite severe.
"It is surprising how large an effect was noticed so quickly, it's perhaps a larger disruption than might have been appreciated."
He cautioned that it was a short-term study so any lasting changes are uncertain, but "you could imagine this would lead to a lot of health-related problems".