As Alex searches for Jeremiah and Kara investigates a series of alien kidnappings, the sisters realize they must break the rules to foil a new Cadmus plot. In an effort to get Snapper Carr to run a story that would help her stop Cadmus, Kara agrees to set up an interview between Snapper and Supergirl.

Alex is kidnapped and the kidnapper threatens to kill her unless Supergirl releases a notorious criminal from prison. Supergirl and Maggie have always had different approaches to apprehending criminals but this time they must work together to save Alex. Meanwhile, Rhea has an interesting proposal for Lena.

When multiple children get sick from lead poisoning, Morgan Edge points the finger at Lena and blames her creation of the lead bomb she made to save National City from the Daxamites. While Lena knows she never intended any harm, she fears there may have been a flaw in her design, leaving her responsible. Kara teams up with Samantha to clear Lena’s name, but it turns out to be harder than they thought. Meanwhile, Alex and Maggie make a crucial decision about the future of their relationship.

Struggling to heal from her injuries inflicted by Reign, Supergirl remains in a dreamlike state, unable to be reached. Mon-El recruits one of the Legion members, Brainiac-5, to try to bring her back. Meanwhile, Reign continues her rampage on the city so the DEO teams up with the Legion of Superheroes to try to stop her.

When Tanya, a disciple of Coville's, escapes from what's left of his cult, she gives Kara and James a journal that could hold the key to saving Sam. Someone learns Guardian's identity and threatens to expose James if he doesn't do what they ask. James contemplates what it means to be a black vigilante without a mask in America.

Nia has a powerful dream about Agent Liberty but refuses to look at it as a prophetic dream and pushes it aside. After noticing something is bothering Nia, Kara enlists Brainy's help, and the two try to persuade Nia to embrace her destiny. Meanwhile, Manchester Black pays Ben Lockwood a menacing visit.

Manchester Black breaks out of prison with the help of his new team, The Elite, who are set on punishing the anti-alien forces. Supergirl pulls double duty as she tries to apprehend Manchester Black and his team as well as deal with a shocking new development with Ben Lockwood.

In the wake of Lex Luthor's return, the show flashes back to what he's been doing for the last two years and how his secret machinations and plans have affected Supergirl and Lena.