NOTE: This spoiler was submitted by David
The film begins at an airport. A Christian lady is attempting to convince a man to accept Jesus Christ. She is cut off in mid-sentence by college student Chloe Steele (Cassi Thomson). The man, who turns out to be Cameron "Buck" Williams (Chad Murray), a tv reporter, is then able to get away. Cameron chases after Chloe and the two begin flirting at a coffee table upstairs.
Soon after Rayford Steele (Nicholas Cage), a pilot, parks his car and walks out into the airport parking lot. He is met by the young blond stewardess Hattie Durham (Nicky Whelan). The two flirt as they head back inside the airport. As they head up an escalator, Rayford is seen by his daughter, Chloe, who has flown in to see her father on his birthday. Cameron realizes introduces himself to Rayford and says goodbye to father and daughter.
Chloe and Rayford discuss Irene Steele's (Lea Thomson), Chloe's mom and Rayford's wife, conversion to Christianity and how they can't stand being preached to. Rayford says he can't stay but that he will see Chloe again. Chloe realizes her dad is leaving to pursue a relationship with the flight stewardess she saw and confronts her father about it. Rayford just hands her the keys to his car and says he needs to board his flight.
Chloe heads home to see her mom and younger brother. Chloe and Irene start chatting and swiftly get on the subject of God. Chloe gets angry and leaves. Her younger brother chases after her and the two head to the mall.
We are then shown the passengers and co-pilot on Rayford's flight. Rayford's co-pilot wishes him a happy birthday. On board the plane a height challenged gentleman attempts to put his luggage in storage. A middle eastern man gets up and offers to help him and the shorter gentleman begins yelling about just because he's short doesn't mean he needs help. Two men in the back discuss the recent invention of a plane that can fly from New York to London in five minutes. Shortly thereafter, the flight takes off for London.
Meanwhile at the mall, Chloe is watching a group of break dancers when she realizes her younger brother is missing. She begins desperately searching for him and finds him playing with a toy plane. The two leave the plane salesman behind with his plane and go to the food court. Chloe tells her brother what a great baseball player he is and the two hug. Mid-hug, Chloe's younger brother is gone. All that remains is his clothes and bag. The same thing has happened to all of the kids and some of the adults in the mall.
Meanwhile, the same thing has happened on the plane. All the kids are gone and some adults including the co-pilot. The horrified passengers begin screaming and a group of three men rush the pilot's room. Cameron, who has been on board the flight, gets up and holds them off. To get everyone to sit down, Rayford turns up the pressure in the cabin and the oxygen masks drop down. Rayford tells everyone to buckle up and put on their oxygen masks. He attempts to radio for help and is unable to reach anyone. The cell phones aren't working either.
Meanwhile, Chloe is still searching for her brother. A car with no driver crashes through the front window. Looters steal someone's money. Chloe gets out into the parking lot where hoards of terrified people are running seeking those who were lost. Cars keep crashing. A one-man plane crashes into Rayford's car just as Chloe is about to get in. Chloe runs down the street and two robbers steal her brother's bag. A school bus crashes off the bridge above Chloe. Chloe runs down to help and realizes that the bus is empty.
Meanwhile, the passengers of Rayford's flight have been able to take off their oxygen masks and are arguing about what might have happened to the other passengers. Theories of alien abduction, wormholes, and that the passengers are just invisible are offered up.
Chloe is running through the streets seeking her disappeared brother. A man is thrown out of a nearby window. Chloe realizes the man is a robber. A man emerges from the building with a shotgun and points it at Chloe. He allows Chloe to run off. Chloe then finds a local hospital, sneaks in past all the chaos, and finds out the room of newborn babies is empty. A nurse appears from behind a curtain and tells Chloe all the hospitals are like this around the world. All of the children in the world are gone.
Rayford sees a plane coming on a collision course toward his plane. He radios the plane and no one responds. After three unsuccessful attempts to radio the other pilot, Rayford manages to dodge the other plane with only slight damage to his plane.
Chloe finds her way home and realizes her home is empty. She sees a Holy Bible on a shelf and throws the book out the window angrily.
Rayford discovers his co-pilot had a watch that said John 3:16. He realizes another stewardess who vanished had her notebook with notes from Bible Study. Rayford realizes his wife was right, the rapture has happened. He attempts to come clean with Hattie, who angrily runs out of the pilot's room. Cameron realizes there is a fire from behind the wing. He comes up to tell Rayford. They realize it's a fuel leak and they are in trouble.
Chloe walls into her mom's church and sees the pastor. The pastor tells Chloe it's the rapture and that he's stuck on Earth because he knew the words but didn't believe any of them. Chloe demands to know why all of the kids and her mom is gone. The pastor tells her that God has taken them out to protect them from the worst time on Earth. Chloe runs out the door in anger.
Rayford asks Cameron to call Chloe. Cameron says he's been trying and hasn't been able to stop thinking about her. Rayford finally reaches someone at JFK Airport on the radio. The JFK radio operator tells Rayford that the airports are full of wreckage and he doesn't know where Rayford will be able to land.
Chloe heads to a bridge and climbs to the top.
The Air Marshal on Rayford's flight gets up and points a gun at numerous people demanding that they explain what's happening. Cameron gets her to calm down and takes the gun. A woman who is addicted to drugs says it's the rapture and she doesn't remember much about it. She learned about the rapture at a church camp when she was a kid and knows God took the disappeared to Heaven but doesn't remember anything else.
Cameron returns to the pilot's room and finally manages to reach Chloe. Rayford apologizes to Chloe and tells Chloe that her mom was right. He then explains the plane is running out of fuel and he doesn't know if he can land the plane. Chloe tells her dad that she will find space.
Chloe runs out and gets a construction site cleared for her dad to land the plane in. She then calls her dad and is able to get through. Rayford tells Chloe he needs a light to find the landing site. Chloe starts a huge fire. Rayford is able to find the field and land the plane.
The passengers come off the plane and one says that the worst is behind them. Chloe says that the troubles have just begun. The film ends as Rayford holds Chloe and Cameron stands nearby.