A mission to steal an ancient sketch pits Syd against her sworn nemesis, a Russian agent who's after the same target. But when the container holding the painting proves impenetrable, the two foes are forced to team up to satisfy their respective agencies. Meanwhile, Will begins to notice something very fishy about Danny's murder; and Francie frets over her guy's possible infidelity.

Sydney and Dixon go on a dangerous case involving the safety of the United Commerce Organization. Francie confronts Charlie about his secret date with another woman, and Will continues to get closer to the truth about Danny's murder.

Sydney must undergo an extensive lie detector test to satisfy Sloane's frantic search for the SD-6 mole. Meanwhile, with nemesis Anna Espinosa following her every move, Sydney seeks out the connection that a device may have to the 500-year-old prophetic Rambaldi sketch. The mystery of Kate Jones deepens as Will continues to investigate Danny's death; and Sydney discovers that a keepsake from her mother Laura contains more disturbing connections into Jack's past alliances.

Sloane temporarily steps down as Director of his Task Force and gives Jack full authority over the next assignment, which involves Anna Espinosa, Sydney's old foe. However, Anna turns the tables on APO when she captures Nadia and forces Sydney to do her biddings. Sydney tells Nadia about the Rambaldi's prophecy which dictates that two sisters will fight and only one will survive. Meanwhile, Vaughn visits Sark and tries to trick him into helping them to catch Anna. In the end, one of the sisters is mortally wounded by Anna.

While Nadia is in a coma, Sark is taken into APO to help them infiltrate Cadmus Revolutionary Front and retrieve the bomb, but in return he demands to see Lauren's corpse and that Vaughn opens her coffin for him. 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.

One month after the baby is born, Sydney is taking time off from work. Will is what pulls her back in the field while she's on maternity leave. The enemies realize that the best way to hurt Sydney is through her friends. Anna Espinosa also returns.