Hotel manager, Lisa Reisert (Rachel McAdams), arrives at Dallas/Fort Worth International Airport to take a red-eye flight back to Miami, Florida. She meets a handsome young man named Jackson Rippner (Cillian Murphy), also traveling to Miami. While waiting to board, they share a drink at the airport bar and engage in small talk.
Lisa is surprised to find that Jackson is seated beside her. After takeoff, Jackson's charming demeanor quickly turns sinister as he informs Lisa that he works for a domestic terrorist organization planning to assassinate Charles Keefe (Jack Scalia), the current United States Deputy Secretary of Homeland Security. Lisa's managerial position at the Lux Atlantic Hotel in Miami, where Keefe and his family are staying, is crucial to their plot. As Acting Manager, Lisa must make a call from the in-flight phone to order the Keefe family be moved to a targeted room where a missile launched from a boat in the harbor will strike. Should she refuse to comply, Jackson's hitman accomplice will kill Lisa's father, Joe (Brian Cox).
Lisa desperately works to protect both her father and the Keefes. When a storm disrupts the sky phone service mid-conversation with her co-worker, Cynthia (Jayma Mays), Lisa pretends to be ordering the room change until Jackson catches on. Lisa makes two additional unsuccessful attempts for help. First, while Jackson is distracted, Lisa writes a warning inside the self-help book she had previously given away to a friendly fellow-passenger (Angela Paton). Jackson head-butts Lisa unconscious and retrieves the book before the woman reads the message. Lisa revives and persuades Jackson to let her use the restroom. She writes a fake bomb threat in soap on the mirror; Jackson, checking on her, sees it and angrily wipes it off, then roughs up Lisa. A young girl waiting outside becomes suspicious and tells the flight attendant that Jackson is inside with Lisa, but it is dismissed as a sexual escapade.
When the sky phones are operational again, Lisa calls Cynthia and has her move the Keefe family to the targeted suite. After, she pleads with Jackson to call off the accomplice waiting outside her father's house, but he refuses until the assassination is confirmed.
As the plane lands at Miami International Airport, Lisa tells Jackson that the knife scar he noticed on her upper chest was from a violent attack she suffered two years ago and which she swore she would never allow to happen again. She then stabs Jackson in the throat with a ball-point pen, grabs his phone, and flees the plane and terminal. Once outside, Lisa steals an unattended SUV. She calls Cynthia, telling her to evacuate the hotel and warn the Keefes. Cynthia, the Keefes, and U.S. Secret Service agents escape seconds before a Javelin missile hits the room.
The cell phone's battery dies as Lisa is calling her father. Arriving at his house and seeing the hitman at the front door, she rams the SUV into it, killing the man. Lisa's father is safe and has contacted 9-1-1. Lisa calls Cynthia, unaware Jackson has arrived and has incapacitated her father. Jackson pursues Lisa throughout the house. As they struggle, he throws her down the staircase. Lisa, stunned, retrieves the dead hitman's gun and shoots Jackson. Wounded, he disarms Lisa and is about to kill her when a revived Joe shoots Jackson with the gun. Lisa returns to the hotel to provide assistance and praises Cynthia for her heroic actions.
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