Glatterflug Flight 627, en route from Hamburg to Boston, flies through an electrical storm over the Atlantic. The passengers inside are in varying states of discomfort bordering on fear, and one passenger looks more troubled than the rest. The sweating man pulls out an insulin pen and injects himself in the stomach. Moments later, the troubled man bursts from his seat. As his skin bubbles and peels, the dying man becomes the apparent source of a horrific contagion that causes passengers' and crew members' skin and muscles to literally melt from their bones.
Boston: A man and women rest in a squeaky motel bed, clearly in the afterglow. It is obvious they are in love, and that they are trying to keep it a secret from the world. A cell phone rings, and the intimate moment is broken as the woman answers. She is Olivia Dunham, a Special Agent with the FBI, as is her partner, John Scott, the man lying next to her.
Olivia arrives at Logan airport, where her friend and co-worker Charlie Francis explains the facts so far: Flight 627 landed by autopilot, and everyone on board is dead. When John Scott arrives, the two of them act professional in front of Charlie, not betraying the intimacy of their relationship.
Meanwhile, an unidentified man drives a van out of Logan Airport. He looks exactly like the troubled man on the flight, the source of the contagion. Can this really be the same guy?
On the tarmac, Special Agent Phillip Broyles of Homeland Security assembles an interagency task force to investigate the case. As the interagency liaison from the FBI, Olivia asks Broyles to include her in the team. There is clearly friction between them, and though Broyles finally agrees, he's not happy about it.
Clad in HAZMAT suits, Olivia and the other agents enter the plane to find the horrifying remains of the passengers - nothing but bare skeletons and oozing puddles of human tissue. What could do this so quickly, and could it happen again?
At the Boston FBI Field Office, agents frantically try to get a handle on what has just happened. Charlie reports a phoned in tip: someone saw a suspicious transaction at a storage facility outside of Boston. Broyles assigns Olivia to investigate.
At the storage facility, Olivia and John uncover a secret laboratory. While Olivia is calling for backup, John spots a suspicious character outside the storage unit - and it's the same man who was leaving the airport! He bolts and John gives chase. The man detonates a failsafe device that destroys the row of storage units. The explosion wreaks havoc, catching John in the blast and knocking Olivia unconscious.
After coming to, Olivia learns that John is suffering from a chemical reaction that is causing his skin and tissue to become translucent - apparently a slow-acting version of what happened to the passengers on Flight 627. The doctors have placed him in a coma to slow the process.
Olivia is now on a mission to find any clue that might save John Scott. Her investigations repeatedly lead back to one name: Dr. Walter Bishop, a scientist whose own research may have provided the basis for the 627 contagion. But Walter has been confined at St. Claire's psychiatric hospital for the past seventeen years. Broyles tells Olivia that if she's going to follow this lead, she'll have to find the only person who has legal access to Dr. Bishop - his son, Peter Bishop.
There's just one catch. Peter is in a Baghdad hotel, and is reluctant to return to the states. But Olivia manipulates him into helping, mentioning his secret FBI file and threatening to let certain people know his whereabouts.
On the flight back, Peter questions Olivia about his father and the work that he used to do for the government. Olivia says Walter worked in an area called "fringe science," covering topics as diverse as mind control, teleportation, astral projection, invisibility, genetic mutation, and reanimation.
Peter escorts Olivia to the mental institution to meet his father. Walter's mind is fractured and his thoughts disconnected, but he does seem to know what might be happening to John Scott. Walter requests to see his son, whom he hasn't seen in many years, and the tension between them is palpable. Peter did not have a happy childhood.
On the way to see John Scott in the hospital, Walter reveals that the only other person who knew about his research was William Bell, his former lab partner. Unknown to Walter, over the past seventeen years Bell has built a multi-billion dollar corporation called Massive Dynamic, and he is now one of the richest men in the world.
Walter examines John, whose condition is worsening. Walter takes a tissue sample and says he needs to examine it in the lab - the same lab he worked in years ago at Harvard. When Peter says that's not possible, Walter becomes agitated and violent. It is clear that no progress will be made without meeting Walter's demands.
Broyles pulls strings to reopen Walter's old Harvard lab.
As the lab is being readied for Walter's experiments, Peter asks Olivia what the FBI has on him, and Olivia admits that she was bluffing. There is no file. She was desperate and needed Peter's help to gain access to Walter. A growing respect begins to form between the two rule-breakers.
Walter explains that the chemical compound used on Flight 627 is similar to one that was developed for use in the Vietnam War. John, however, was exposed to the compound's raw ingredients, and in order to synthesize a cure, Walter needs to know exactly what chemicals were in the storage unit. But the storage unit was completely destroyed in the explosion, and John was the only one who saw the suspect.
Walter proposes a dangerous gambit. He recalls an experiment involving the retrieval of memories from a person who had been dead for less then six hours. He posits that the same method could be used to merge two people's consciousness - thus providing access to the comatose victim's brain. However, the procedure will involve dosing Olivia with a drug cocktail - including LSD. Despite the danger, Olivia agrees to proceed.
Once the preparations are complete, Olivia strips down and enters an isolation tank. Outside the tank, Walter, Peter, and Astrid (Olivia's assistant) watch monitors as John's and Olivia's brainwave patterns merge, indicating a subconscious connection between the two.
As their minds meld, Olivia enters a surreal dream world. The scenery changes again and again until she stands in a graveyard facing John Scott. They embrace, and clearly they are still passionately in love. Olivia asks John to remember the face he saw at the storage unit. Through John's eyes, Olivia relives the events at the storage unit. Just before the inevitable blast, Olivia sees the suspect's face! Her vitals spike and the tank doors fly open as Walter and Peter lift her out.
A computer rendering of the suspect's face leads them to a passenger who was on Flight 627, Morgan Steig. But everyone on the flight died. It turns out that Morgan has a twin brother, Richard Steig, and Richard's last employer was Massive Dynamic.
Olivia pays a visit to Massive Dynamic and is received by the firm's Chief Operating Officer, Nina Sharp. Nina hands over the company's file on Richard Steig, while giving Olivia a chilling warning about the world of fringe science she is now investigating.
Olivia and an FBI tactical team swarm Steig's apartment while Walter and Peter wait outside in a car. When Steig escapes out the back, Olivia gives chase, and with Peter's unexpected help she apprehends Steig. Back at the FBI, Olivia interrogates Steig, trying to get the list of chemicals that he used to create the contagion. When Steig refuses to talk, Peter steps in and reveals his willingness to use violence to get answers.
In the lab, Walter and Peter concoct a formula based on Steig's information to reverse John's condition. As Olivia waits outside, Broyles approaches her and extends an olive branch. He says he wants her to come and work for him, on a special task force investigating "The Pattern," a series of bizarre events involving unexplained phenomena and rapid scientific progress. It is as if someone is conducting experiments, but with the whole world as their lab. Olivia refuses the offer, intent on returning to her familiar life. Broyles pointedly replies that that may not be possible.
With John in recovery, Olivia checks in on Steig. He tells Olivia that there is a mole in the FBI; someone from her office contacted him trying to buy the contagion. When Olivia demands proof, Steig gives her directions to an audiotape. Olivia retrieves the tape, and as she listens to it she recognizes the mole's voice. It's John Scott!
Meanwhile, John has recovered enough to get out of bed and change into street clothes. He immediately goes about tying off loose ends, the first of which is Richard Steig, whom John smothers with a pillow. Olivia pulls up to the hospital just in time to see John fleeing in a car, and a high-speed chase ensues. The chase ends in grisly wreck as John's car flips over. As he crawls from the wreckage, Olivia demands to know who he is really working for, but before John can answer he dies in her arms.
In the aftermath, a conversation with Charlie makes Olivia realize how much the world has changed. And she knows what she has to do. Returning to Harvard, she finds Walter about to return to the asylum. She intercepts Peter and urges him to stay, because only Peter can watch over Walter and speak his language. Walter's understanding of fringe science may be the key to unraveling the mysterious string of events known as The Pattern. Peter reluctantly agrees.
Back at Massive Dynamic, Nina Sharp observes John Scott's lifeless body on a gurney. She asks an orderly how long John has been dead. The answer is five hours. Nina gives the order: "Question him." The body is wheeled silently through a high-security portal for the interrogation to begin.