Sawyer discovers just how far his captors will go to thwart any plans of escape he and Kate might have, and Jack is called upon to scrub up in order to save the life of one of "The Others." Meanwhile, Desmond's behavior begins to perplex the survivors when he starts construction on an unknown device.
Lena’s ex-boyfriend, Jack Spheer (guest star Rahul Kohli), 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.
When 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 she planned after she meets her new boss, Snapper Carr (recurring guest star Ian Gomez).
When an attack is made on the President (guest star Lynda Carter) 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. While Alex teams up with Detective Maggie Sawyer (Floriana Lima) to investigate the case, Kara searches for a recently escaped Mon-El (new series regular Chris Wood), 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 (guest star Dichen Lachman), 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 (guest star Sharon Leal) better. Supergirl takes Mon-El under her wing and begins to train him.
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