Cadmus attacks National City with a Kryptonite-powered villain who ends up seriously hurting Supergirl. Superman blames J'onn because the Kryptonite was stolen from the D.E.O.. Meanwhile, Kara's first day at her new job doesn't go as planned after she meets her new boss, Snapper Carr.
Supergirl and Superman arrive to a burning building. Supergirl uses her super-breath to quell the fire as Superman flies fast enough to create a rain cloud over the building. The firefighters look on in awe. The two of them then respond to a robbery, stopping the thieves' car. The thieves fire bullets at the Kryptonian heroes but they have no effect and are easily knocked out. J'onn then directs them to a Kigori in Riverside Park. At headquarters, Alex and Winn notice J'onn's grim demeanor with having to deal with Superman in town.
A woman wakes up John Corben from his operation. Corben realizes that he has enhanced strength. The woman explains that she is a doctor working for Cadmus who offers him to save the world from aliens.
At the D.E.O., J'onn chastises Kara for having too much fun with Clark and not following protocol. A power surge hits the building. Winn says the source is the holding area with the comatose alien. They figure out that the alien is using electrical energy to repair himself at a cellular level. After J'onn and Clark get into another spat, Kara tells J'onn to get along with Clark while he is in town. Alex reminds Kara of their sister night. Kara tells Alex she invited Clark.
Kara reports to CatCo for her first day on the job as a reporter. Cat Grant introduces Kara to her new boss, Snapper Carr, who runs CatCo Magazine's investigation team and who doesn't seem too interested in his new stringer.
At Kara's apartment, Clark tells Kara he will be heading back to Metropolis. They see a bridge jumper on the news and leave for the bridge. They arrive and discover it's actually Corben, now introducing himself as Metallo, who hits Clark with a beam from the kryptonite core in his chest. Supergirl punches him to no effect. Metallo holds Superman in a choke hold. Supergirl fires her heat-vision but Metallo blocks it with his cybernetic hand. Supergirl takes cover behind a car as Metallo fires kryptonite beams at her. Supergirl jumps on top of the car but is struck by Metallo's beam. Superman then hits Metallo sending him flying away in the distance. Superman carries Supergirl in his arms and flies her back to the D.E.O. Clark confronts J'onn about the kryptonite, who admits that a D.E.O. shipment of kryptonite went missing months ago and that there may be a mole within the agency touching off a heated argument between the two. Suddenly, all of National City's computers and televisions are hacked and a broadcast from Cadmus declares war on all aliens.
In Snapper's office, Snapper tells off Kara for missing the editorial meeting and that she hasn't earned a place in his office. Snapper tells Kara to get out of his office. Kara goes to Cat to get her help, but Cat tells her that Kara needs to deal with him on her own. Cat then tells her that she taking a leave of absence from CatCo which Kara doesn't take too well.
The woman from Cadmus tells her associates that the incident on the bridge wasn't a total failure and that she plans on proceeding to Phase Two. She instructs her lackeys to restrain Gilcrist and take him away for modification.
At the Fortress of Solitude, Clark and J'onn resume their debate. J'onn reveals that he speaks Kryptonian and tells Clark that both of them have no homes and the importance of preserving each other's histories. Clark says he doesn't hate J'onn, just that he can't trust him so long as he keeps kryptonite. Clark has Kelex scan his hand for residual materials from his fight with Metallo. Kelex discovers residual promethium.
Kara tells Alex that she wants to move to Metropolis to be with Clark. Alex confesses that she has stayed silent since Clark has been in town and confesses that she needs Kara so that they can protect each other. Alex tells her that protecting her all these years has cost her a lot.
At the D.E.O., J'onn has Winn trace the promethium and finds Metallo in the industrial district. Superman and Supergirl knock down Metallo but Metallo tells them that another man is terrorizing Metropolis. They fly to Metropolis to see Gilcrist's trail of destruction.
Winn and Alex are working on the anti-kryptonite suits. Winn tells Alex of his experience of living in foster homes and says that being family is not about keeping score, but simply showing up. Winn and Alex then come up with a plan to use a geiger counter to determine which D.E.O. agent stole the kryptonite. In the locker room, they identify agent J. McGill as the mole. Alex tasks McGill with readying a transport of kryptonite for transfer. Kara later walks into the D.E.O. and forces Winn to tell her where Alex went.
Alex catches McGill with the kryptonite and points her gun at him. Before Alex can arrest him, the woman from Cadmus appears from behind and shoots him. Alex questions the woman about her father's whereabouts. The woman tries to convince her to join Cadmus and to imagine her life if aliens hadn't come to Earth, but Alex declines. The woman gestures to her guards and leaves. Alex knocks over the guards and runs from their gunfire. Alex pins one of them down but the other points his gun at her. Supergirl crashes down from the ceiling and catches the bullet. They both knock out the guards and Kara apologizes to Alex for making her fell like she was prioritizing Clark over her.
At the D.E.O., Winn shows them the completed anti-Kryptonite suits. Kara comes up with a plan to stop both Metallos. Superman engages Gilcrist/Metallo in Metropolis and Kara engages Corben/Metallo in National City. The anti-kryptonite suits withstand both Metallos' chest beams. Supergirl and Superman fight the Metallos in their respective cities. A well placed punch by both Metallos disable the anti-kryptonite suits weakening the Kryptonians. Martian Manhunter then comes to Superman's aid and helps Superman dispatch Gilcrist by punching out his kryptonite heart. Alex comes to Supergirl's aid and uses a mech-suit to go toe-to-toe with Corben, stabbing Corben in his kryptonite heart.
Supergirl then pays a visit to Cat before she leaves. Cat is excited to leave but Supergirl tells her to come back eventually, which Cat promises to. Supergirl then leaves to the CatCo office and speed-changes into regular clothes. James tells Kara that he is taking Cat's position while she is away and offers to talk to Snapper for Kara but Kara insists on dealing with him on her own. Kara turns in her article on the Metallo attacks to Snapper. Snapper doesn't think much of the article but he tells her to return tomorrow.
At the D.E.O., J'onn turns over all of the department's kryptonite to Superman. Clark says goodbye to Alex, Winn, and Kara. Superman then leaves with the kryptonite and heads to Metropolis. Clark receives an angry call from Perry White for his absence.
Kara sits by the comatose alien's bedside. The alien suddenly wakes up and clutches Kara by the neck.
- The episode's title refers to Kal-El/Superman and Kara Zor-El/Supergirl, as they are the last children of Krypton to survive it's destruction.
- While Winn is tracking Metallo, the molecule that pops up, C12H22O11, is the molecular formula for sucrose, which is table sugar.
- Clark holding Kara's body is a reference to the cover of Crisis on Infinite Earths #7.
- Metallo pretending to commit suicide is a reference to Justice League: Doom.
- When Alex tells Kara, "I gave up a medical career to join the DEO for you", she could be referring to Chyler Leigh's previous role as Lexie Grey in the show Grey's Anatomy.
- When Alex is captured by Lillian, she mentions having stabbed Astra, who she says is a member of the House of El. This is incorrect as the only links Astra had to the House of El were through Alura and Kara as Alura was the wife of Zor-El and Kara was an heir to the House of El alongside her cousin, Kal-El.
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