As Dixon struggles with the death of his wife, He refuses to take time off from work until Sloane is brought to justice. But Sydney worries that Dixon's repressed rage could cause more harm that anything Sloane could do.

Sydney must confront her mother, who tells a clue about "some Rambaldi artifacts" in Zurich, but it was a trap to capture Jack. As Sloane keeps Jack hostage, Vaughn and Sydney go to Stockholm to capture Sark, who reveals the hideout in Mexico City. Meanwhile, Tippin discovers that Francie is in fact a "double" and is the one who framed him...

Having woken up in Hong Kong, with no memory for the last two years (!), Sydney returns to Los Angeles to try to piece together the last two years of her life and discovers the fates of her friends and family: Vaughn has married thinking that Sydney was long dead; Marshall is having a baby with CIA tech expert Carrie Bowman; and Dixon is now the new division head of the L.A. office branch of the CIA. Sydney also learns the shocking fates of Jack and Sloane; the former is in CIA custody for communicating with Irina whom still is in hiding, while the latter is living in Switzerland under house arrest in exchange for co-operation with the CIA. Sydney is granted temporary CIA clearance on a case that may help her regain her memory and she meets a new enemy group called The Covenant.

Sydney discovers a link to her missing two years in the form of Simon Walker, the dangerous leader of a group determined on retrieving deadly biological weapons. Meanwhile, Vaughn struggles with his own feelings of jealousy and longing while Sydney is on her mission, aware of the pressures his job is putting on his marriage to Lauren. Jack takes matters into his own hands to protect his daughter, and purposefully revealing Sydney's deadly secret of being a brainwashed assassin for the Covenant during her two-year absence to Dixon in order to preserve her position inside the CIA.

Sydney and Vaughn are sent to retrieve the Doleac Agenda to gain an advantage over The Covenant. For this, Sydney and Weiss must convince rogue security systems designer Toni Cummings to help the CIA break into a Lethal Response System. Meanwhile, Sark approaches an unlikely ally, that of Lauren Reed, to kill the Covenant's six cell leaders in order to take control of Covenant for themselves.

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.

Four months after Vaughn's murder by the traitorous Gordon Dean and his associate Ivan Curtis, a grief-stricken Sydney teams up with Renée Rienne, a French freelance assassin and fugitive on the CIA's most wanted list who knew Vaughn from their past association with Prophet Five, to ask for leads in order to track down the killers before they can strike again. Meanwhile, Jack enlists a reluctant new agent, Thomas Grace, as Vaughn's replacement at APO, and Weiss struggles to decide whether or not to accept a promotion that would force him to move to Washington D.C. and leave his colleagues at APO. During this time, Sydney, Dixon and Weiss travel to Amsterdam to track down Curtis who is in the process of buying a potential weapon.

Sloane takes Rachel and Marshall hostage to force them to help him find the Rambaldi clue that he is missing. Sydney, Vaughn and APO try to save them by having Marshall's wife, Carrie, to help out, while Sloan plots with Sark and Peyton to take over Prophet Five for themselves.