The heroes must come up with a way to defeat Reign without killing her. Afterward, Winn and Alex get job offers, Mon-El and Hank make decisions about their personal lives, and James has a news story for the world.

Supergirl and Mon-El try to get to Earth to stop the Daughters of Juru from resurrecting Reign and triggering Earth's destruction. Meanwhile, Hank participates in The Reach with his father, and Ruby demands the truth from Sam.

Kara and Mon-El return to Argo City, but not all is as it seems. Meanwhile, in Supergirl's absence, Guardian and the DEO deal with a dangerous gunman wielding DEO weaponry.

Supergirl and Mon-El find a remnant of Krypton drifting deep in space. Meanwhile, Alex faces a killer from her past, and Winn ends up babysitting Ruby.

Followers of Coville plan to use his journal to create a new Worldkiller. Meanwhile, Supergirl tries to repair the rift between her and Lena, and James is forced to consider whether to out himself or not.

Lena provides Alex with a safehouse to protect Ruby from Reign, who is looking to severe the last ties of humanity that Sam has with her family. Meanwhile, Supergirl discovers that Lena has been manufacturing Kryptonite, and the Legionnaires depart for the future.

Supergirl discovers that she has a mental link to Sam and Julia, and takes Lena and Alex with her to rescue them. Meanwhile, James faces a tough decision when he must decide whether to investigate Lena or not after she kept Reign's existence a secret.

The third Worldkiller, Pestilence, begins striking down the citizens of National City.... including Winn and Alex. Supergirl and Imra disagree on how to deal with Pestilence, and Lena continues trying to find a cure for Sam.

M'yrnn tries to redirect his mental processes and ends up infecting the DEO with a telepathic rage virus. Meanwhile, Lena tries to convince Sam that the latter transforms into Reign during her blackouts.

After Winslow dies, his wife Mary comes to National City to attempt to reunite with Winn. However, a new murderous toymaker threatens Winn and Mary, Meanwhile, M'yrnn asks Alex to keep a secret from Hank, and Mon-El tries to find the right time to tell Supergirl something important about one of the Worldkillers.

The DEO easily captures Julia Freeman, the second Worldkiller Purity's body. While Supergirl and Alex try to get through to her, Mon-El asks Hank for his help repairing the Legion Cruiser.

Morgan believes that a recent attempt on his life was made by Lena. When Lena is poisoned, Kara steps in to find out who is responsible for the escalation in hosility. Meanwhile, Sam turns to Alex for help determining the cause of her blackouts.

Supergirl and Saturn Girl are forced to recruit two female metas to find a prisoner on Fort Rozz, which is orbiting a sun that emits radiation fatal to males. Meanwhile, Alex babysits Ruby while Sam goes on a work trip.

Mon-El and Imra decide whether to help the DEO battle Reign. Meanwhile, another Legionnaire attempts to help Kara emerge from the coma that Reign put her into after their battle.

Supergirl learns that a mysterious Kryptonian symbol suddenly appearing around the city heralds the appearance of the World Killer, Reign. She's a Kryptonian whose powers exceed Supergirl's... and who is determined to bring judgment to a sinful world. The tension between Lena and Morgan Edge continues to build.

Rather than wallow in self-pity, Kara and Alex go to Barry Allen and Iris West's wedding... only to find the ceremony interrupted by Nazi soldiers and villains from Earth-X including a mysteriously strong superpowered female warrior.

The DEO rescues Mon-El from a spaceship buried in 12,000 years of rock, but Mon-El remains strangely silent about how he got there. Meanwhile, Hank takes M'yrnn to the park, and Sam goes to her mother Patricia for answers about her birth.

Kara takes Alex home to Midvale after Alex and Maggie break up. While Alex deals with the end of her relationship, she and Kara remember the first time that they bonded as sisters while solving the murder of a fellow high school student.

Morgan accuses Lena of poisoning the children of National City with the lead bomb she used to drive off the Daxamites. Kara and Sam work to clear their friend's name. Meanwhile, Maggie and Alex break up.

Kara learns of a cult-like organization of people that she's rescued... who consider her a god. Meanwhile, Sam has difficulty balancing her career with her personal life.

Supergirl goes with Hank to Mars in response to M'gann's telepathic request for help. Meanwhile, Maggie invites her estranged father Oscar to her and Alex's wedding shower that's sponsored by Eliza.

Supergirl faces Psi, a thief who can psychically induce her victims' worst fears. Meanwhile, James deals with having a new boss at CatCo, and Alex and Maggie continue making plans for their wedding.

After losing Mon-El, Kara decides to give up her human life and dedicate herself full-time to being Supergirl. Meanwhile, a new menace threatens National City, and real estate mogul Morgan Edge makes a bid to buy up CatCo. Also, Alex confesses a secret to Maggie, a citizen of National City has a mysterious connection to Kara, and Lena makes a bold move.