Opening on a dark evening, Agnes White (Ashley Judd) is a 30-something woman living in a run-down motel in rural Oklahoma. She is smoking a cigarette outside of her motel room when her phone rings. She answers it, but no one says anything. Flustered, she goes about her business, but her phone keeps on ringing. Every time she picks it up, no one says anything. She thinks that it's her ex-husband Jerry Goss, since he just got out of prison and she has a restraining order against him. However, she can't confirm this because the caller never says anything. The next morning, she goes outside and finds a flier for a body shop on her windshield, also noticing that none of the other cars have the flier. She throws it away and goes to the grocery store to buy some food and alcohol, where she is startled by a man reaching for a bottle.
That evening, Agnes goes to work where she's a waitress at a lesbian bar. Her best friend and co-worker Ronnie 'R.C.' (Lynn Collins) startles her, and they talk. Agnes wants to come over to R.C.'s house after work, but R.C. tells her that her lesbian live-in lover is fighting a custody battle with her ex-husband for custody of her children and that R.C.'s and Agnes' presence would be a bad influence, but they argree to meet at Agnes' motel room later. R.C. wants to introduce Agnes to a man standing at the jukebox, but Agnes is wary to get back in a relationship so soon.
Later that evening, R.C. and Peter Evans (Michael Shannon) arrive at Agnes motel room. The two women drink, smoke dope, snort cocaine, and even make out with each other, but Peter is shy and quiet. While Peter uses the bathroom, they joke that he's probably a serial killer. R.C. gets a phone call and talks loudly while Peter insists that he's not a killer. He's awkward around Agnes, and things get more awkward when he tells her that she's beautiful. R.C. tells them that she has to go back to the bar due to a problem, so she takes off while Peter decides to stay.
Agnes asks if Peter would like a drink, but he says that he should probably go. They talk while they walk outside of the motel, getting to know each other better. Agnes asks him if he's gay because he took little interest in her makeout session with R.C., and he says "no". He explains that, like Agnes with R.C., he has experimented with the same sex, but he does not consider himself gay or bisexual or bi-curious like she is. Peter doesn't consider himself much of anything, and claims that he has been alone for a long time. When she asks Peter where he lives, he says that he's "kind of living in-between places" (coded talk meaning that he's homeless). She offers to let him stay the night, and he accepts. While Agnes gets ready for bed, we see that Peter's experiencing some pain in his tooth. During the night, as Peter lays on the couch and Agnes on the bed, Peter looks at the ceiling fan and hears helicopters. He gets up and asks Agnes if she wouldn't mind if he slept on the floor. As they both lay in their places, neither can readily go to sleep.
The next morning, Agnes gets up and hears him in the shower. She goes to the kitchen and pours herself some coffee. As he gets out of the shower, Agnes thanks him for making coffee. However, it's not Peter in the shower... its her ex-husband Jerry (Harry Connick Jr.). He gets dressed and gets in an argument with Agnes. She doesn't want him there, and when she brings up their son Lloyd, Jerry smacks her across the face. He doesn't ever want her to bring up his name again, and then Peter returns. Jerry acts very tough around Peter, who appears very weak. Eventually, Jerry warns Agnes that he'll be back and leaves.
Peter helps her sit down and gets a rag to hold against her bloodied face. He gets her some aspirin, and takes some himself for his tooth. He tells Agnes that he left earlier to get some breakfast for them at a diner just down the road, and apologizes for taking her motel room key. Agnes tells him about Jerry, and how abusive he can be. Peter asks her if she has a son, and she says she doesn't. Peter knows that shes lying, and she eventually tells him that her son went missing while she took him shopping at a grocery store. She gave up looking for him two years ago, and becomes very emotional when talking about him. She tells Peter that he can stay another night, since she gets afraid at night. Even though he hasn't been with a woman in a long time, Peter says that he would like to go to bed with her.
They have sex, and in the middle of the night Peter gets up and turns on a light. He just got bitten by a bug, and he searches the bed for it, waking Agnes up. He finds the bug on the bed, but Agnes can't see it. He holds a lamp with one hand and the bug in another, but she still can't see it. Agnes wants to go back to sleep and tells him that its just a bed bug, but Peter tells her that its not. Its an aphid; plant lice. He tries to explain it to her, but all it does is confuse her. Peter searches the bed for more aphids and gets Agnes to help him. She loves hearing Peter talk, and then he tells her that someone's after him. He refuses to tell her why, and gets dressed in a hurry. Peter doesn't want to get Agnes caught up in his troubles, so hes going to leave. Agnes tries to get him to stay, since she's lonely and doesnt have that many friends. Peter leaves the room and runs away from the motel.
Agnes breaks down and cries in the bathroom. Peter comes back and talks to her through the bathroom door. He tells her that he was in the U.S. Army, and that people have experimented on him. He doesn't know what he's infected with, but she might have it too now that theyve had sex. He breaks down and cries, telling her that hes sorry and explains how vicious the scientific experiments were. He escaped from the army, and they have been after him ever since. He decides to stay with Agnes, and they embrace as they hear helicopters near them, which violently shake the room.
The next day, Peter has changed the motel room. Fly catchers hang from the ceiling in every room, along with blue bug zappers. He's taken out Lloyd's possessions because he had a microscope, and takes a blood sample from his finger (which he inspects with the microscope). Jerry breaks into the room using a credit card, and Peter startles him. Agnes isn't there, but Jerry has decided to move in. He talks down to Peter, who constantly slaps his own body for bugs. Jerry doesn't see anything, and Peter sees that there are bugs in his blood. Agnes and R.C. enter the room, and both of them get upset that Jerry's there. Agnes and Peter force Jerry to leave after he's rude to everyone. Peter tells Agnes that there are bugs in his blood, but R.C. keeps on talking over him (which upsets him). He tells her that she has bugs in her too, and Agnes says that theyre underneath her skin. R.C. doesn't see any bugs anywhere, but Agnes decides to show her by cutting into her arm with a paper clip. R.C. tells Peter that they went to the hospital, and the doctors didn't find anything wrong with Agnes. Peter's upset that she went to see a doctor, and R.C. tells them that there's nothing wrong with him either. Peter lifts up his shirt and shows that his body has several scratches on it.
R.C. tells Peter that a man came in to see her at the bar, looking for him. The man's name is Dr. Sweet, and wouldn't tell her anything else specific. Peter grows upset that Dr. Sweet knows where he is, and that R.C. can tell him whenever she wants. R.C. tells Agnes to pack her stuff, and wants her to come live with her for a while (regretting ever introducing them to each other). Peter then takes off his shirt and starts to swat bugs around him. R.C. still can't see anything, but Peter convulses on the bed. R.C. and Agnes wrap him in blankets until he calms down. Agnes then slaps R.C. in the face for trying to take her away from Peter. She tells her to leave and never come back. Shocked, R.C. gets her stuff and leaves the room.
Later that night, Peter lies down on the floor, resting his head in Agnes' lap. Even though they haven't known each other for a while, she can't get over how much she loves him. We see that Agnes now too has several scratch marks all over her body. Eventually, Peter comes to the conclusion that he was infected with bugs as part of an experiment, and that they placed several eggs in his tooth. Peter grabs a pair of pliers and rips out his tooth. Agnes wants him to stop, but he then goes to the bathroom and rips out more of his teeth. Very bloody and in much pain, Peter examines his tooth through the microscope and cowers in terror. Agnes looks through the microscope and sees millions of bugs in his tooth.
A little later on, Dr. Sweet (Brian F. O'Byrne) approaches the room and knocks on the door. When he does, we see that the room is only lit by the blue bug zappers, and everything is wrapped in tin foil. He tries to convince Agnes to open the door, and she gradually crawls her way towards the door. Jerry bursts into the room and holds her down. Dr. Sweet tells him to leave, saying that he'll handle this. Jerry waits outside, and Dr. Sweet asks where Peter is. Agnes won't tell him, since he told her that Dr. Sweet is the one who experimented on him. Dr. Sweet informs Agnes that Peter is a delusional paranoid, with schizophrenic tendencies. Dr. Sweet claims he's here to help, but she's convinced that he just wants to take him back to the army to conduct more experiments. Dr. Sweet sees a glass pipe on a dresser, which appears to be for smoking crystal meth. He asks Agnes how often she uses it. She says that she takes it whenever she wants, and Dr. Sweet asks her permission to smoke some. He sits down and starts to fire it up when Agnes tells him to be careful, since he's sitting on gallons of gasoline. After smoking a bit, he tells her that he needs her help to take Peter to get help. Medical professionals can operate on Peter and get the bugs out of him. He then tells Agnes that he knows where her son is. Agnes asks if he's alive, and Dr. Sweet nods 'yes'. He will tell her where Lloyd is, if she helps him. Peter then comes out of the bathroom, very bloody from wounds on his chest and face. He holds Dr. Sweet at knife point while Agnes tells him that he knows where Lloyd is. Dr. Sweet prepares a needle behind his back, but before he can do anything with it Peter stabs him in the chest. Peter continues to viciously stab Dr. Sweet to death.
Agnes grows hysterical and asks why he killed Dr. Sweet. Peter says that Dr. Sweet is not a human, but an android sent by the army. Agnes doesn't believe him, but Peter insists that Dr. Sweet has artificial blood and that he's a robot. He then goes on a psychotic rant, explaining that every human has been injected with a computer chip at birth since 1982 and that the army has been choosing specific people to be test subjects. During the rant, Peter also says that the microchip turns people into brainless killer zombies, and that Timothy McVeigh was one of them. He figures that none of this is a coincidence, and that Agnes was brought into the situation on purpose. He forces her to think about what she knows that she may not know. More paranoid than ever, Agnes comes to the conclusion that Lloyd was kidnapped by the army, and that the bugs were part of a weapons experiment. We see that the phone is disconnected and hear someone knocking on the door. It's a pizza delivery guy, and they freak out since neither remembering ordering any pizza. They slide money beneath the door and tell the delivery guy to just leave the pizza on the ground. Very cautiously, Peter opens the door and Agnes grabs the pizza. Before they can eat any, Peter grabs a piece and inspects it through the microscope. He sees bugs on the pizza and flips out.
They come up with a conspiracy that R.C. is working for the army, and purposefully brought them together so that the experiment could be further carried out. Peter is the drone, and Agnes is the queen bug. They hear helicopters and the room begins to violently shake as they both maniacally laugh. Jerry tries to break his way inside the room, but they block the door with the bed mattresses and Agnes injures his hand with a staple gun. The room shakes uncontrollably from the army helicopters, but Jerry is the only one outside. Fully insane, Peter and Agnes douse the room with gasoline. They then strip naked and douse themselves with gasoline, convinced that they have to kill themselves to prevent the spread of the infection from getting out of the room. Peter and Agnes profess their love for each other. Peter strikes a match, setting themselves on fire and destroying the room as it's immediately consumed by flames.