CADMUS attacks National City with a Kryptonite-powered villain who ends up seriously hurting Supergirl. Superman blames Hank because the Kryptonite was stolen from the DEO. Meanwhile, Kara’s first day at her new job doesn’t go as planned after she meets her new boss, Snapper Carr.

An attack is made on the President as hot-button, alien vs. human rights issues heat up in National City. Supergirl and the DEO are assigned to protect the President and bring in the responsible party. Alex teams up with Detective Maggie Sawyer to investigate the case while Kara searches for a recently escaped Mon-El, who she fears may be the alien behind the assault.

When Kara and Alex investigate the murder of an unregistered alien, the trail leads to an alien fight club run by Roulette, the ringmaster who commands aliens to fight in mortal combat for the entertainment of rich humans. While trying to stop the fighting, Supergirl and Martian Manhunter find themselves up against a surprising opponent. Meanwhile, Hank is thrilled to have found another Martian and tries to get to know M'Gann better. Supergirl takes Mon-El under her wing and begins to train him.

While Guardian tries to clear his name after being accused of a murder committed by another vigilante, Supergirl heads out on a solo mission to rescue Mon-El who has been captured by Cadmus. While fighting to free Mon-El, Supergirl comes face to face with Cyborg Superman.

Kara is moved by the story of a missing woman named Izzy and decides to investigate despite Snapper Carr's order to leave it alone. Kara takes Mon-El with her to the last place Izzy was seen and the duo find themselves thrust through a portal to another planet, Slaver's Moon, where the downtrodden are sold as slaves. The leader of the trafficking ring is none other than Roulette. To make matters worse, Slaver's Moon has a red sun, which means Kara and Mon-El are stripped of their powers and stuck on the planet with no way home. Meanwhile, back on Earth, Alex blames herself for Kara's disappearance, fearing she's become too focused on her new relationship with Maggie and too complacent in watching out for her sister.

After Metallo breaks out of prison and frees Lillian Luthor, the police blame Lena for his escape and arrest her. Despite overwhelming evidence, Kara refuses to believe her friend is guilty and fights to clear Lena’s name. Flashbacks reveal how Lena came to be a Luthor.

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.

Lena’s ex-boyfriend, Jack Spheer, comes to National City to unveil his big breakthrough in nano-technology, which has the potential to eradicate all diseases. Lena asks Kara to attend Jack’s conference with her for support. When Kara sees Snapper in attendance she’s inspired to tap back into her reporter skills and questions Jack on his discovery, which ultimately leads to a bigger investigation that puts everyone in danger.