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's search for her past leads to an imprisoned Sark, but their Q&A is cut short when he becomes the ransom for a pair of abducted CIA scientists by the Covenant, whose kidnappers may be tied to the murder of his father. Meanwhile, Jack contacts an old friend of sorts for info on Sloane's new world-peace project in Switzerland. Also, Vaughn makes a decision about his future as an operative for the CIA.

Sydney's emotions are turned inside-out when she once again comes face-to-face with Allison Doren, the murdered Francie's doppelgänger, who was presumed dead but is now a key assassin working for the Covenant. Meanwhile Lauren's search for Lazarey's murderer leads her closer to discovering the connection to Sydney, and Sydney begrudgingly is assigned as Sloane's CIA handler.

When Sydney is taken into custody by the NSC honcho Mr. Lindsey, Jack and Vaughn have no choice but to ally themselves with Sloane to rescue her. But with only hours to spare before she is forced to undergo a radical surgery to recover her memories, they must put together an extraction team, headed by freelance operative Brill. Meanwhile, Lauren faces an impossible choice: side with the NSC who she wants to believe is doing the right thing, or with her husband in their rescue of Sydney.

After making a shocking discovery of a severed human hand in the desert that belonged to Lazarey, the Russian diplomat she murdered while working as a brainwashed assassin for the Covenant, and who may in fact be alive, Sydney agrees to submit to an experimental procedure conducted by an eccentric doctor, named Dr. Brezzel, designed to retrieve her lost memories. But while Jack and Vaughn look on, Sydney's mind proves surprisingly resistant to letting her remember her missing time... and the process of recovering it could end up killing her. Meanwhile, Lauren makes a great sacrifice of allowing herself to get tortured and beaten up in order to make her alibi believable to Lindsey after helping breaking Sydney out of NSC custody. Also Sloane finds himself boxed in by an unlikely enemy, that of Mr. Lindsey, who wants to see Sydney Bristow eliminated permanently.

The identity of the mysterious "St. Aidan" forces Sydney to pull a stunned Will Tippin out of witness protection for help in finding Lazarey to clear her name. But the pursuit sends the two old friends on a collision course with Allison, the Francie impostor who ruined both their lives. Meanwhile, a jealous Lindsey arrests Jack and Vaughn as conspirators in Sydney's escape from NSC custody. Sloane, still under pressure from Lindsey, puts a plan in motion to eliminate Sydney, and Dr. Brezzel has an unpleasant run-in with Sark whom is also looking for Sydney.