Two months after the destruction of both the Primatech and Pinehurst, and the death of Arthur Petrelli, the now-villainous Nathan returns with a vengeance by persuading the U.S. President and the government to round up all people with abilities for containment and disposal, leading to Claire, Ando, Peter, as well as Tracy to become fugitives from the people who were their former allies. In Japan, a powerless Hiro tries to live through the super-charger Ando as his latest partner. In New York, Peter struggles to find a life for himself as a paramedic, but finds that his cannot hide from his past. Claire learns about Nathan's and Angela's plans for interment of people with abilities and sets out to warn Matt Parkman who learns more about his abilities from the spirit of the African spiritualist Usutu. Elsewhere, Syler travels to Baltimore to locate his long-lost father and ends up being the only one who escapes from a government dragnet led by a mysterious agent known only as 'the Hunter'. Mohinder also learns that he has been targeted, and that Noah Bennett is apparently working with Nathan as well.

Following the plane crash, the surviving heroes must team up with one another to try to survive the manhunt. Claire is quickly captured by Noah who takes charge of a "kill squad" to find the remaining people with abilities while Nathan deals with the overzealous 'hunter' Emile Danko whom becomes obsessed with tracking down all people with special abilities in his own lethal way. Mohinder and a powerless Hiro must rely on Matt Parkman's spiritual guide to help them. Daphne makes contact with Ando to help her find Matt, unaware of the people now targeting them. In New Jersey, Syler takes refuge in the house of an agent and tortures him to try to get information to what's going on and he forms an unlikely alliance with the agent's son Luke Campbell. Also, Peter teams up with Tracy to look for help, while she begins having second thoughts about running.

Imprisoned inside the super-secret 'Building 26' which is Nathan's base of operations to experiment and terminate people with abilities, Tracy struggles to survive various "heat" experiments as well as wait for an opportunity to try to escape. While the ruthless Hunter Davko obsessively continues to track down the heroes with the obsession of killing them all, Nathan deals with the President of the USA who begins to investigate Nathan's activities and tactics to hunt down the "targets". Meanwhile, Syler continues his quest to locate his biological father with both help and inference from Luke Campbell, as well as government agents now after both of them. Hiro, Ando, and Matt travel to India to find a new ally with abilities to help them survive. In California, Claire faces the wrath of her father.

Peter, Matt, and Mohinder drug and abduct Noah "H.R.G." Bennet and hold him captive in a seedy motel room so Matt can interrogate him to find out more about the people hunting them down, but predictably, it does not go as planned as Benett plans to turn them against each other, while Nathan and the sadistic Danko are looking for him. Noah's background story is revealed about how Nathan approached him to help the government's plan to round up people with special powers, and his awkward alliance with Danko who has his own agenda... as does Nathan.

Following a tip from their anonymous source "Rebel", Matt and Peter hurry to rescue Daphne from the holding facilities in 'Building 26' in Washington, and to find evidence that may expose the government's plans to capture those with powers. Meanwhile, Sylar uncovers the truth about his mother after he experiences past memories of his father at a disused diner located deep in the New Mexico desert which makes him dump Luke and head off to look for his biological father. In California, Claire must find a way to sneak Alex out of her house which is under observation by FBI Agents, and Mrs. Bennet reluctantly agrees to help. Elsewhere, Danko hatches another nefarious and explosive plan of his own to trap and kill Matt. Also, Claire has a run-in with an old villain, Eric Doyle, whom she captured a while back who asks for her help to hide from government assassins after him too.

Now on his own, Sylar finally finds his biological father, Samson Gray, a reclusive, lung-cancer ridden taxidermist, to confront him with questions about his past, but soon learns that Samson is not who he appears to be. Meanwhile, Nathan continues to lock horns with Danko over the hunter's tactics to eliminate people with abilities, after he tries to frame Parkman for an attempted suicide bombing. This leads to both Nathan and Danko going behind each others back to unseat the other. Nathan becomes wary about Danko going rogue and the hunter interrogating Tracy, as well as Nathan's mother, Angela, about Nathan's own ability. In California, Claire takes Alex's old job at the comic book store where she is given a message by 'Rebel' to help out her former nemesis, the puppet master Eric Doyle, when he too is targeted by rogue agents. Also, Hiro and Ando return to California where they are led by clue from Rebel... to an infant Matt Parkman.