The Season Two opener, "Red Rain," continues the action from last season's finale when Anna unleashed Red Sky on the planet. With the world on the brink of war and chaos all around, is there anyone who can stand up to Anna? Meanwhile, Ryan has been kept in isolation on the mothership, away from his hybrid baby so that Anna can experiment on her. Chad, seeking redemption for being used by Anna, now wants to fight with the Fifth Column, and Erica goes on a journey to find a scientist who can give her the answers to what Red Sky is, and where she learns the horrifying secret of what the Vs are doing on our planet.

Anna and Diana square off in the dark bowels of the Mothership – Diana has been down there for 15 years and not had a single glimpse of Anna. Meanwhile, Erica has Tyler's blood analyzed, and learns the Vs did something sinister to her when she was pregnant with him.

Erica learns her partner, Malik, is a Visitor and must fight for her life – literally – to stop Anna from finding out she's Fifth Column. Meanwhile, Anna learns that Malik is missing and orders Ryan to find her, while Lisa realizes her body is beginning to change, causing her to become more and more like her mother.

Erica, seeking revenge against Anna, heads to Hong Kong to carry out a mission to strike a lethal blow against Anna. Meanwhile, Anna learns that Tyler's phosphorous level is too low – even after the Red Rain – and he might become useless to her; and Lisa and Diana bond, beginning to form an alliance against Anna.

Erica, now officially in charge of the global Fifth Column, leads them in a high risk attack against Anna. Anna meanwhile, growing closer in her plan to destroy humanity, finds a major obstacle in a certain Live Aboard candidate; and Ryan sneaks back onto the Mothership to try and rescue his daughter.

Anna is about to pull the switch on the planet's first Blue Energy reactor, but Sid realizes that the size of the reactor is much too large for just the various Concordia sites – the Fifth Column needs to figure out what Anna is really up to. Diana tells Lisa she must act against Anna now, fulfil her destiny and save humans from annihilation.