Five months later. Sydney quits the CIA and joins a Black Ops unit called "Authorized Personnel Only" alongside Dixon, Jack, Vaughn and... Sloane whom for limited immunity is co-operating with the APO. Meanwhile, the truth Sydney found out in Wittenberg endangers her relationship with Jack, and eventually she reveals the awful truth to Vaughn: about her father having Irina murdered over a year earlier.

Sydney unwillingly teams up with her father to hunt down a modern-day samurai, named Kazu Tamazaki. Meanwhile, Nadia is back home in Argentina and refuses to go back into the spy business. But she is forced to when Sydney's life is jeopardized when she's taken captive by the brutal Tamazaki. Sydney finds out the reason behind Jack's misdeed and Nadia makes an unsettling promise to Sydney to find out who murdered Irina.

Sydney must seduce Martin Bishop, a murderous arms dealer in order to track down a stolen NSA code-breaker. Meanwhile, Vaughn fears for Weiss's life, and Sydney and Jack argue with each other about telling Nadia the truth about her mother's death.

Sydney and Vaughn go undercover to track down a deadly new bio-weapon. Meanwhile, Sydney is concerned about Vaughn not having yet put Lauren behind, and Nadia turns to a Jack to ask for his help in finding out the truth about her mother's murder, who tries to throw Nadia away from the evidence pointing to him.

Sydney and Vaughn go undercover as an arms dealing married couple in a mock-up setting of American suburbia to find a stolen electro-magnetic pulse weapon that when detonated, could bring back the Dark Ages. However, the neighborhood they've infiltrated is not as charming as it seems for the other "happy couples" of this American suburbia setting in Russia could spell trouble for them and their cover.

When Sydney gets bitten on the neck by a missing in action CIA agent, she soon finds out that she has been infected by a experiential hallucinogen, causing her to slowly lose touch with reality. Vaughn and Jack must race against the clock to find an antidote before Sydney puts her life (and others next to her) into danger.

While Sydney and Nadia argue about Nadia's acceptance of Sloane's fatherly concerns, Sloane worries about Nadia's well-being when she and Sydney go undercover as wealthy, irresponsible young Hilton-type heiresses to uncover the whereabouts of a deadly chemical from a playboy arms dealer.

Sloane temporarily steps down as director of his APO task force and gives Jack full authority over the next assignment, which involves Anna Espinosa, the former K-Directorate assassin and Sydney's old foe into racing her to go after stolen classified documents. However, Anna turns the tables on APO when she captures Nadia and forces Sydney to do her bidding. During this time, Sydney tells Nadia about the Rambaldi's prophecy which dictates that "two sisters will fight, and only one will survive." Meanwhile, Vaughn visits the imprisoned Sark and tries to trick him into helping them to catch Anna.

While Nadia is in a coma after being shot by Anna, Sark is taken into APO to help them infiltrate the Cadmus Revolutionary Front and retrieve the stolen bomb, but in return he demands to see Lauren Reed's corpse and that Vaughn open her coffin for him. Sydney learns that the comatose Nadia may be the only person with the Intel they need to intercept the bomb, so Jack is forced to prematurely wake Nadia from her coma, endangering her life, which doesn't please Sloane when he finds out.

Dixon secretly enlists Sydney to help him prove that Sloane is double-crossing the CIA and using APO to steal the Blackwell Index, a master blackmail list, and to reconstruct the Alliance of Twelve. Sydney makes her way into Sloane's house so as to copy the encryption key from his secure phone and crack his phone calls. When Nadia finds Sydney snooping around Sloane's computer, she doesn't tell him, but becomes disappointed in her sister and begins to lose trust with Sydney. Meanwhile, Vaughn discovers something disturbing about his late father when he visits his comatose, dying uncle who makes a remark about seeing his father - recently.

During a mission to Austria, Sydney must protect the life of an American civilian, whom she unintentionally put in danger after she acquires information about a new mini-helicopter to be used as a weapon. Meanwhile, Jack travels to Madagascar to visit with an old friend, the arms dealer Sasha Korjev whom is the mastermind behind the assassin helicopter. Back in Los Angeles, Vaughn uncovers more disturbing secrets about his father of finding a diary with notes written years after his alleged "murder," which straightens his quest to know if his father is really alive.

Nadia puts her own life (as well Sydney's and Weiss's) in danger after failing to unveil her past about her involvement with a dangerous criminal, named Ceasar Martinez from her home in Argentina whom recruited her as an assassin for his gang and wants to relive old times. Meanwhile, Vaughn finds a person who is somehow connected to his father and Nadia as well.

When a mission to Cuba goes wrong, Sydney is attacked and placed in serious danger of being buried alive in a sealed coffin. Back in Los Angeles, Dixon is exposed to a deadly pathogen released inside APO which is currently in lock down due to the toxin and Marshal (not being in the building at the time due to his home life problems), is the only one who can get to Sydney and save her. Only with com link help from Jack, Vaughn and the others at APO, the socially awkward and field inexperienced Marshal has to finish a very important mission on his own before it's too late.

Vaughn and Sydney, searches for Vaughns father, and the word Nightingale. Getting help from her father, telling him that Vaughns father might still be alive. Jack Bristow and Sloane have their own agenda. Following Jack Intel, Sydney and Vaughn goes to Munich. Dressed as a German beer maid, Sydney roughly pursued an investment banker to give her information. They find out that Nightingale is still an active experiment, in an atomic plant in Siberia. They go on a mission to the plant. Which turns out to be very dangerous for both Sydney and her father.

On his own and desperate to find out more about his supposedly-dead father, Vaughn is pressured into a rogue operation for an unknown organization in exchange for information on the whereabouts of his father. He gains more than he bargained for in the deal. Meanwhile, Nadia is meeting with her aunt, Katya Derevko, in order to learn more about her mother, but Sydney doesn't trust Katya's motives.

Sydney and Vaughn tell Jack about Sloane's alleged involvement in Vaughn's search for his father and Irina's contract on Sydney's life. After cornering Sloane, they both conclude that someone is framing him. The APO team set a trap to catch the fake A. Sloane, but they fail. Once they realize what "Arvin Clone" is after, Sloane suggests to step down, temporarily. However, Sydney reluctantly convinces him to stay on the case, since he may the only person able to anticipate "Arvin Clone"'s next move. But Nadia fears that this pursuit may revive her father's past obsession: Rambaldi.

Nadia's former caretaker, Sophia, has been severely beaten. She contacts Nadia and asks to meet her. Sloane is told by Sophia that she was beaten up, because someone is trying to track Nadia down, so he and Jack decide to tell their daughters the truth. It turns out that Elena Derevko, the third and the cruelest of the Derevko sisters, has been surveying both Sydney and Nadia for a decade. Meanwhile, Jack's doctor advises him to tell Sydney about his illness.

Jack's illness has caused him to hallucinate about a cure among other things. As a result, Sydney must recreate the time when Jack was working for the CIA and hid the only man who might be able to help him now. For this, Sydney must role play her own mother. Meanwhile, Sophia moves in with Sydney and Nadia.

Sydney and the rest of the team finally capture the Sloane impostor and bring him to APO where they question him to find a rare Rambaldi orchid whose pollen has some miraculous capabilities with a Rambaldi device. However, the real Sloane must relive a painful memory with his late wife Emily in order to get the Imposter Sloane to reveal the orchid location.

After a tactical group infiltrates the DSR and steals all the Rambaldi artifacts, CIA director Hayden Chase discovers that the alarms at the DSR were disabled from Nadia's computer, allowing the raid to happen. Mrs. Chase shows up at the apartment to question her. Soon Sloane and Jack arrive and suspect that Sophia, who had access to the computer while she was living with Sydney and Nadia, is in fact Elena Derevko. They follow her trail to a dead Rambaldi follower, a stunning betrayal, and a presumed dead family member when in a surprising twist, Sydney and Nadia learn that Irina Derevko is in fact alive.

Rambaldi's catastrophic endgame begins to fall into place as a giant red ball version of the Circumference/Mueller device is found floating over a large city in Russia, driving the citizens mad with violence. After a wounded Dixon reveals that Irina is alive, Sydney, Nadia, and Jack set off to find her. It turns out that Irina had been captured, and then duplicated using Project Helix, in order to give the impression that she was dead. Sydney and Nadia discover Irina being held inside a camp in Tikal, safely in the clutches of Elena's private army. Irina had apparently been working to counter Elena's organization, the Covenant, and actually PREVENT the Rambaldi endgame. Irina is taken to APO and tells them of a page she destroyed, a page that was key to Rambaldi's endgame. Under torture, she finally broke and recreated it for Elena. After a short respite, Sydney, Vaughn, Jack, Nadia, and Irina board a plane parachute down, towards Elena, Sloane, the Circumference....and destiny.

Jack, Sydney, Irina, Vaughn and Nadia parachute into Sovogda, Russa to dismantle the giant floating red ball of the Circumfrence which is turning people into mindless, red-eyed zombies out to kill. Back at APO, Marshall and Weiss try use the Blackwell Index to blackmail the Russian defense minister into giving them the access codes to a Russian satellite before the local authorities plan to drop a nuclear bomb on the city to destroy it and prevent the spread of the contagion, and they also discover that Elena is up linking the satellite. In the ruins of the city, a CIA agent, Brodien (the one whom Sydney rescued from Shanghai in the season opener) reminds them that the Rambaldi device is broadcasting a sub audible frequency that physiologically alters people who drink the water-like fluid that has infected the city's water supply and it is irreversible. At the same time, Elena learns of the APO team's arrival and sends Sloane and her men to go out to kill them, leading to a three-way war between Elena's henchman, the APO group, and the zombies leading to Nadia becoming infecting and having a final one-on-one confrontation with Sydney atop a building with the red ball Circumference in the balance.