The film opens with Chev Cheelios (Jason Statham) waking up in his bed. Something’s wrong, and he feels like crap. He stumbles around his apartment and finds a DVD titled “Fuck you” in front of the TV. When he plays it, he sees Verona (Jose Pablo Cantillo) bragging on and on about how he injected him with a poison in his sleep. The cameraman shows Chev asleep in his bed, and we see Verona inject him in the back of the neck. Verona’s brother knocked him out with a baseball bat to make sure he wouldn’t wake up. Chev only has about an hour to live. Chev, full of rage, smashes his TV and storms out of his apartment while grabbing his cell phone. He calls his girlfriend Eve, but gets her answer machine (she doesn’t have a cell phone). He calls Doc Miles’ (Dwight Yoakam) office, but he’s away in Vegas partying with hookers and will be back later that day. Chev makes his secretary take down a message (“DEAD Cheelios”). His heart starts to slow down, and Chev experiences intense pain. He slams his foot on the gas and he feels a bit better. He calls Kaylo (Effren Ramirez) and asks him where he was last night (he was dressed in drag at a club). Chev tells him to put the word out that he’s looking for Verona, and that he should call him if he finds him.
Chev speeds off to Orlando’s (Reno Wilson) place, where he bursts into the building looking for him. He holds him at gunpoint and shoves him into the bathroom, while Orlando’s Sin City Deciples gang follow and all point their guns at Chev. He wants to know where Verona is, but Orlando doesn’t know. After everyone gets calm, Chev’s health starts to fail again and he holds himself up against a wall. He buys some cocaine from Orlando and snorts it on the bathroom floor. He then thinks back to when his heart was failing, but got better once he floored his car. Chev says “I know what I have to do I have to kick some black ass!” and headbutts one of Orlando’s goons. He starts to pick a fight with them all, but they throw him through the front door and he speeds off again.
He eventually gets a hold of Doc Miles, who from Chev’s description comes to the conclusion that he has been poisoned with a Beijing cocktail. Basically, it’s feeding off his adrenaline. If his adrenaline becomes too low, he’ll die. Cops starts to chase Chev as he speeds through the city in his car while talking to Miles on the phone. Miles tells him to keep moving, and to make his way to a hospital. They have epinephrine, which is artificial adrenaline. He tells Chev though that he shouldn’t take a whole needle full of it, as too much will kill him. Miles says to only take a small amount, but Chev’s a bit preoccupied by driving through a mall with the police right behind him to fully pay attention. Chev somehow manages to crash his car sideways on an escalator, and then starts to run away on foot. Miles is on his way back to LA and will be there in the afternoon. He wishes him good luck and hangs up. Chev pushes some people out of a cab and tells the cabbie to drive. His heart starts to fail again, so he makes the cabbie crank up the volume on the radio. After trying unsuccessfully to get pumped while listening to “Achy Breaky Heart”, he makes the cab stop in front of a convenience store. Chev storms in, pulls the cashier out, and holds him at gunpoint. He then proceeds to grab a bunch of red bulls and other energy drinks. Somewhere along here Eve calls him back. Turns out she was home the entire time but was being lazy. He says that he’ll be over soon, and tells her to make some waffles.
Chev gets back in the cab and makes him drive to Beverly Hills. We see Carlito (Carlos Sanz), a big crime boss, enjoying his day with half-naked girls and heavily armed guards. Carlito jumps into his pool to have Chev jump in as well, who signals him to go to the surface. Chev works for Carlito as a hitman, and asks him for help. Carlito laughs at him, and says that there is no antidote for the poison. Turns out Carlito and Verona are going to do business together, so he won’t help him. Carlito tells Chev that he shouldn’t have killed Don Kim, his last target. Chev leaves the pool and goes back to the cab. The cabbie won’t let in, since he’s soaking wet, so Chev pulls him out and throws him on the ground. He yells out “Al Qaida!” and points at the cabbie, which prompts a nearby crowd to jump him and start breaking his bones. Chev drives away in the cab and gets a call from Kaylo, who just spotted Verona’s brother at a restaurant. Chev drives there, makes sure no one else went inside with Verona’s brother, and enters the restaurant. He makes his presence known and signals for the brother to follow him outside. The brother pulls out his pistol and looks for Chev, who grabbed a butcher’s knife. Once outside, Chev cuts off the brother’s hand and demands to know where Verona is. He won’t tell, and tackles Chev onto the ground. He punches him with his other hand, but misses when he tries to hit him with his bloody stump. Kaylo comes out and distracts him. Chev pulls the trigger for his gun but it won’t work (from his pool meeting), so he grabs the guy’s severed hand which still has the finger on the trigger. He blows Verona’s brother through the back of the head, killing him and spraying Kaylo will blood and brain matter. Chev calls Verona (who’s in the middle of getting a bj) and informs him that he just murdered his brother. He takes his necklace and promises to throw it away, but it’s of family importance to Verona. Chev hangs up and heads to the hospital.
He goes straight to the pharmacy and forgets what the artificial adrenaline was called. The receptionist is of no help, saying that they can’t sell it to him. When she leaves, a tweaker (Chester Bennington) tells Chev to use nose spray, which has some epinephrine in it. Chev grabs as many as he can and walks throughout the hospital, snorting nose spray. The receptionist told some cops about him, and they start to chase him in the hospital. Chev sneaks into a room, takes off his clothes except for his shoes/socks, and puts on a hospital gown. With his cell phone in his sock and his pistol in his armpit, Chev starts to get away when the cops notice him again. He ends up running into some paramedics rushing someone on a stretcher through the hallways. Chev figures that they would have some epinephrine, so he follows them and holds one of the doctors (Glenn Howerton) at gunpoint. Chev shoots at the following cops and orders the doctor to give him epinephrine. When they stop at an elevator, the doctor finally finds it and gives it to Chev, who gets another idea. He orders the doctor to shock him with the defibrillator. It’s so powerful that it knocks Chev clear into the open elevator. That might not have been such a good idea, as it did more damage than good for Chev. Nonetheless, he loads up a shot of epinephrine and injects it into his arm. Then he realizes that he forgot how much Miles told him to inject (he did the whole thing).
Hopped up on epinephrine, he runs out of the hospital like a madman and runs everywhere. Miles calls from his second plane home and asks if Chev injected himself yet. He figures out that he took too much, and asks his symptoms (among which, include tightened muscles and a mega boner). When Chev eventually stops, he sees a bunch of people watching TV sets describing the chaos Chev has already done. They show the public a police sketch of Chev (which makes him look insane) and says that he is still at large. One of the TV watchers notices Chev, and his enormous boner. Chev tries to play low-key, but in a hospital gown he stands out like a sore thumb. He sees a police officer on a bike at a red light. He snatches the cop’s gun, and toys around with him over it. When he throws it away, the cop goes for it while Chev steals his motorcycle. The cop tries to hold on to the back of the bike, but can’t keep his grip. Chev speeds off, but finds that his heart is failing again. He decides to stand on top of the bike with his arms outstretched. He enjoys his ride, until the bike crashes and Chev lands into a bunch of tables in a restaurant. When he comes to, he continues on his way to Eve’s home.
When he shows up, he’s wearing a running outfit that he stole and Eve asks him to fix her microwave clock while she gets dressed. The microwave gets mundane quickly, and Chev’s health fails. In a desperate bid, he slams his own hand onto the hot stove, burning his hand. Eve says that he’s so stressed out, and asks if he wants some weed. Meanwhile, Verona doesn’t want to wait for Chev to keel over so he sends over a couple of his goons to Eve’s apartment. Right before they leave, Eve hears the phone ringing and answers it. No one talks, and so Chev runs out to the front, where a goon is calling from. He bashes his head and runs back to Eve’s apartment. When they go to the parking lot, Chev purposefully spills out everything from Eve’s purse so that she’s preoccupied while he fights with another goon. The goon tries to shoot him and Eve, but misses and blows apart a pet bird. Chev breaks his neck and grabs his gun. Chev says that he took a cab there, so they’ll have to take Eve’s car. They drive to Chinatown, where Chev explains that instead of being a video game programmer (like he told her), he’s a professional hitman. She doesn’t believe him, and he begins to recount the Don Kim job. Chev perfectly snuck in and had Don Kim in his sight, but just couldn’t kill him. He wanted to give up his job for Eve, and spared Don Kim (telling him to disappear for a couple of days). Chev tells Eve to go somewhere as well, without him. Eve, taking this as a break-up, storms out of the restaurant.
She doesn’t believe anything he just said, about the poison and killing. Chev’s health fails again, and he tells Eve to have sex with him right now, in the middle of Chinatown. She refuses, and he collapses. When she climbs on top of him to see if he’s okay, he comes to again and kisses her. Eve’s into it now, and wants him to have sex with her in front of everyone. Chev tries, but can’t get it up. Eve’s pissed, but he picks her up and pumps her from behind while she’s leaning on a newsstand. The crowd of people watching, including a bus full of Asian schoolgirls, cheer and clap while Chev yells “I’m alive!” a couple of times. He gets a phone call from Kaylo, who says that he knows where Verona is. Chev repeats the location out loud, and stops having sex. He tells Eve that he’ll see her later and runs off, leaving her embarrassed in front of everyone.
We see that Kaylo is actually caught by Verona’s henchman, and they have him tied to a chair. They put a plastic bag over his head and suffocate him until he’s dead. Chev gets a cab, and the Haitian driver tells him that he better not die in his car (he thinks he’s a cokehead). The driver gives him some crazy Haitian drugs, saying it’s hardcore. Chev figures what the hell and takes it. He starts to hallucinate and comes to when they get to the location. He pays the driver and walks to the building, but knows something’s wrong. He gets onto the roof, where he recognizes one of the goons. He throws him off the roof, then gets to the level where the others are. Verona’s boys tells Chev that Verona just wants him to go to a dark place and just die. His publicity isn’t helping anyone, and they try to kill him. Eve shows up in an elevator just in time to see Chev start killing everyone. He uses Kaylo’s body as a shield while he makes his way to the elevator. He gets shot in the leg and it finally dawns on Eve that he wasn’t joking about his job. They go to a lower level, where several people are making clothes. Chev gets a goon’s hand stuck in a needle machine and runs off with Eve. They go down a stairwell and Chev shoots another guy. He lets the body drop to the ground before he takes off with Eve.
The remaining goons give chase in their cars while Chev drives Eve’s. Chev explains again that he needs to keep his adrenaline up to stay alive. Eve gets an idea, and proceeds to give Chev a blowjob while he’s driving. He shoots at a car that drove up to their side, which makes it crash into a park car. Eve stops before Chev can climax, saying that she doesn’t want him to sleep like he always does. Chev gets pissed and uses it against the last car. He makes it crash, then walks across the street and unloads his gun into the last goons. Chev drives to Doc Miles’ office, where he hooks him up with some more epinephrine. Miles explains that he can keep him hooked up for a couple of days, in time to find out the antidote. He says that he will eventually fall into a coma, and offers to drug him up so that he dies in a nice dream. Chev doesn’t want to go out that way, and calls Verona to again brag about killing his brother. He says that he will exchange his brother’s necklace for the antidote (knowing that there isn’t one). Verona agrees, and they set up a meeting at a hotel. Miles hooks up Chev with a portable device which helps keeps the epinephrine running through his veins. Chev asks him to not tell Eve his chances.
Chev walks down the street in a suit, and the scenes intercut with him saying his last goodbye to Eve. He gets to the hotel, where he goes to the bathroom and checks his portable device (along with his pistol). He gets in an elevator with an Asian man, and starts to hallucinate again. He imagines the man talking back to him using different voices (his mother’s, his own, Eve’s, Verona’s, e.t.c…). The guy thinks he’s weird and exits at his floor. When Chev gets to the top floor, two goons take away his gun and bring him to the roof, where there are girls in big bubbles and more armed henchmen. Carlito and Verona are waiting for Chev, and Verona orders another pat-down for him. They find his portable device and rip it out. Verona has another needle full of the poison, and wants to inject Chev with it again to make sure he dies. Chev (drugged out) makes a gun with his finger and points it at a goon’s forehead. He then points it at Verona and Carlito, making a goat sound. Everyone thinks he’s crazy, and when Chev fires his finger gun at a goon he actually does get shot……by Don Kim and his gang, who have come to fight for Chev. A big shootout occurs, and many people on both sides get killed. Police have gathered on the ground, along with news people. A newscaster says that the man responsible for today’s mayhem is making his last stand on the roof, where they hope to get a news helicopter up there to show uncensored footage of the shootout. One of Don Kim’s crew throws a grenade at Carlito, but he tackles one of his goons on top of the grenade. It explodes, covering Carlito in blood and guts. Chev shoots Verona, which causes his gun to somehow blast off his fingers. Verona runs off with the poison, and Chev gives chase while trying to shoot him (his aiming is off due to the drugs). Carlito gets to his helicopter on the roof, and orders the pilot to take off. Chev catches up to him and tries to kill him, but Verona injects him again with the poison. Chev collapses, and Verona shoots Carlito to death. He orders the pilot to lift off. Chev comes to and grabs onto the helicopter as it takes off.
Verona and Chev fight as they hover high in the sky. Verona tries to shove and kick Chev off the helicopter, but he keeps on hanging on and punching Verona. Chev grabs Verona and causes both of them to fall out of the helicopter. While falling, they continue to fight until Chev grabs Verona’s throat and crushes it with his bare hands. Verona dies and falls faster than Chev, who grabs his phone and calls Eve. It’s her answer machine again, and he apologizes for letting her down again by not keeping his promise of staying alive. He tells her that it seems all his life he’s just been letting people down, one after another. He hangs up and continues to free fall. Chev lands on top of a car, which causes him to bounce off it of it and lands hard on the ground. Chev’s eyes bleed and twitch as he dies.