John is packing for a vacation to see the world while Karen wonders if he might have trouble with his claustrophobia. She gives him an 8-Ball as a going away present and suggests what he's looking for might be in Seattle – John is skeptical.
John boards the plane and has some initial problems with his claustrophobia and recites plane facts to try and calm himself. He also meets a men's weight-lifting team from Euthania including Pavel and his daughter, and meets some of his fellow passengers, including a model, a flight engineer, and his neighbor, a neurologist named Rachel Penbroke. She loses her speech that's stored on her laptop and John manages to retrieve it for her. She uses neural pressure on his hand to help him relax and he dozes off as they head into the air.
Later Rachel wakes John up for dinner and they share a drink as a priest staggers into the cabin, gasping, and collapses. One of the passengers take charge and thinks it was a stroke, but John asserts out it's murder. The passenger, Inspector Tate Garrison of Scotland Yard, disputes John's assertion but John quickly shows it's poison. They talk to the priest's neighbor who knows nothing and says he went to sleep, woke up, and then had his attack. John suggests they investigate but Garrison overrides him until John cites the appropriate Federal law that allows him to take over.
Garrison reluctantly compromises and talks to the passengers while John has the weight-lifting team move the priest's corpse. and John and Rachel do an impromptu autopsy using the model boyfriend's camera lens. They find a puncture mark on the back of his knee and the scent of strychnine, but the hole is so small it couldn't be a syringe. Looking under the seat, they find a small pressurized piston designed to shoot the priest in the leg by remote control. John accidentally injects himself and collapses.
Fortunately there's only a little poison in the injector and John recovers after they siphon it out. They organize into teams to search the plane and Rachel offers to help John with his amnesia, but he's not interested in being studied. The flight attendant reveals they have another problem – the co-pilot went into the lavatory a half hour ago and hasn't come out. They bust in and find that he has died a messy death, a pen thrust into his neck.
Garrison seals the crime scene while they try to open the flight cabin when the captain doesn't respond and the plane hits some turbulence. The cabin door is locked and reinforced, but John goes to the flight engineer and uses his laptop to run a decryption program to open the keypad lock. When that doesn't work, John figures it's water damage from the sink where the co-pilot died and the water flooded. John goes through a rear access panel to get at the damaged circuits, barely dodging a loose cargo crate and fastening it back into place. He manages to hook up the circuits and they get into the cabin, where the pilot is unconscious from carbon monoxide poisoning when the air scrubbers short-circuited.
John has no choice but to take over as pilot. With the controls acting erratically, John improvises a level flight indicator from a bottle of booze, and stabilizes the plane so the autopilot can take over. They have 45 minutes to Heathrow and John and Rachel share a moment as she reveals her parents died when she was 10. Garrison agrees they can check out the dead co-pilot, who apparently caught the killer doing something. John checks out the lavatory and finds the hidden remote for the injector. John plans to test the range of the remote to determine the killer's seat. They narrow it down to 20' and a specific section of the plane, and Garrison interrogates the passenger.
John wonders why the poison was so painful and suspects a personal motive. That doesn't jibe with the minister who seems unlikely to have any enemies, and notices the victim was moved. The killer was trying to murder someone else and was in the adjacent section where he couldn't see his intended victim. They examine the manifest and find the minister was moved and the original passenger's name was crossed out. John uses aftershave to create a solvent to erase the ink and find that Rachel was the original passenger in the seat. John panics and goes after her and the passengers think John's the killer and lock him in another lavatory. John panics while the flight engineer begins to slink off.
While Rachel tends to the co-pilot, John has a small walkie-talkie he picked up in his pocket, and manages to talk to the daughter of one of the weight-lifters. He frees John who brings Rachel up to date and asks her to identify anyone who might want to kill her. John has the weight-lifter protect Rachel and goes to meet with Garrison. John figures the killer has washed off the blood from stabbing the co-pilot, but can use bio-luminescence to spot the blood. John uses hair bleach and photographic developer to make a chemical spray to react with the blood, then use a palm pilot light for luminescence to spot the blood. They check the first-class passengers' hands and they all prove clean. John checks Garrison's hands and they indicate blood…but there's no splatter – he got the blood on his hands from moving the killer, as does John.
John checks with a flight attendant who notices they're missing someone . John goes over the list and notices a Louis Garber is missing – the flight engineer. They go to check out Rachel, who is missing and the weight-lifter is knocked out. Garber has Rachel down in the hold with the hatch open – he has a mask but she doesn't. Garber relates how his mother died when she was in Rachel's test program and he was going to use the poison to give her the same agonizing death his mother suffered from. When John arrives Garber threatens to use a flare to destroy the entire plane. John releases the crate, from earlier, crushing Garber.
The plane touches down and Garrison takes credit for solving the mystery, although the weight-lifter quickly makes sure he gives credit where credit is due. John and Rachel have a quiet moment and he notices she's getting a divorce because she keeps twisting at a non-existent ring, but Rachel says he's wrong and tells him he'll have to fix her dinner to find out, and they kiss.