|"Things were looking a little grim, but part of me was, admittedly, a little excited for a "reunion" of old friends."|
- For the eponymous virus, see Medusa virus.
- "In the event of an invasion, Medusa could be deployed to kill alien combatants while keeping our civilians and infrastructure safe from harm."
- —The hologram of Zor-El to Kara on Project Cadmus' virus
|Eliza comes to town to celebrate Thanksgiving with her daughters. Alex decides it's time to come out to her mother, Kara is shocked when Eliza suggests Mon-El has feelings for her, and Winn and James consider telling Kara the truth about the Guardian. Meanwhile, Cadmus unleashes a virus that instantly kills any alien in the vicinity so Kara enlists an unexpected ally - Lena Luthor. The epic superhero crossover kicks off tonight when Barry Allen and Cisco Ramon seek Kara's help with an alien invasion on their Earth.|
- Melissa Benoist as Kara Danvers/Supergirl
- Mehcad Brooks as James Olsen
- Chyler Leigh as Dr. Alex Danvers
- Jeremy Jordan as Winn Schott
- Floriana Lima as Detective Maggie Sawyer
- Chris Wood as Mon-El
- David Harewood as Director J'onn J'onzz and Hank Henshaw/Cyborg Superman
Special guest stars
- Byron Brisco as Security Guard
- Keisha Haines as Human Waitress
- Serge Jaswal as Navigator
- Marisa Nielsen as Cute Alien
- Kirsten Virus as Giggles
- Josh Hallem as Brian
- Robert Zen Humpage as Fish Head
- Erika Walter as Female
Kara is using her heat vision to defrost the Thanksgiving turkey. James and Winn tell Alex they are planning to tell Kara James is Guardian but Alex insists she has more important news. Mon-El arrives and charms Eliza. Kara thinks he is hitting on her but Eliza thinks he is doing it because he likes Kara. In the end, no-one is able to make an announcement because a portal briefly appears and disappears over the dinner table during the toasts.
Next day, Winn confirms to Supergirl and Alex at the DEO that something ripped the space-time continuum apart. J'onn reminds them that they still have the question of why Cadmus wanted Supergirl's blood. Alex and Winn want to hack Lena's files to see if she knows anything. Supergirl prefers to talk to her but they do the hack anyway. Kara visits Lena claiming to be doing an article about the influence powerful women's mothers had on them. Lena says she was never good enough for her mother. After Kara has gone, Lena meets with Lillian and tells her a reporter is asking questions about her. They also exchange awkward comments about Lillian never treating Lena like one of the family.
Mon-El goes to the alien bar, where he shows no interest in an attractive alien female who tries to chat him up. A hooded Henshaw places a device under the bar. Mon-El follows him out and Henshaw overpowers him. The device releases a gas that kills all the alien patrons in the bar.
Mon-El is placed in quarantine at the DEO while Alex and Eliza work on analysis the virus. J'onn also thinks he and Supergirl should stay there since the virus seems to affect non-humans. Supergirl keeps Mon-El occupied with a game and asks him if he has a crush on her. He denies it, then collapses. He is infected but not contagious: The virus gas needs to be breathed in. Eliza realises the virus is Kryptonian in origin. Supergirl realises her blood was taken to get access to the Fortress of Solitude.
Supergirl flies to the Fortress and is attacked by Kelex, who has been reprogrammed to view her as an intruder: she destroys it. A simulation of Zor-El tells her that Project Medusa was a virus he created to defend Krypton from attack: If they were invaded, it could be used to wipe out all non-Kryptonians. Supergirl is disgusted and shares the news with her friends. Mon-El is still alive because of his similarity to Kryptonians but eventually the infection will kill him. Eliza tells Alex she already knows she's gay, because she knows when she's keeping secrets and because of the way she talks about Maggie. Eliza is fine with it.
Supergirl confides in J'onn about her disillusionment about her parents. J'onn tells her she is her true legacy. He partly transforms into a White Martian and tells her about the blood transfusion. He doesn't want anyone else to know, since they need to concentrate on Medusa. Alex and Eliza have checked the Kryptonian files and discovered a delivery system is used. The closest Earth analogy is Isotope 454, developed by L-Corp. Supergirl flies there while Alex asks Maggie to send a squad.
Henshaw has already attacked L-Corp. Supergirl stops him harming a security guard and also Lena when he throws a chunk of masonry at her as she stumbles onto the scene. Henshaw gains the upper hand, which even Maggie's arrival with back-up doesn't change, but is distracted by another briefly appearing portal. He flees after wounding Maggie with his laser vision.
Supergirl tells Mon-El it was her parents that created the virus. Mon-El kisses her, then passes out. Alex patches Maggie up and tells her about coming out to Eliza and how she's realised it is about being true to herself. Supergirl goes to see Lena and tells her about Lillian being the leader of Cadmus and releasing the virus, asking her to help find her. Lena accuses her of being another person who thinks the worst of Luthors, despite Supergirl insisting she thinks Lena is a good person. Lena meets with Lillian again, saying she knows about the virus and her sending Henshaw. She says Lillian only had to ask, producing a case of isotope 454.
Winn detects the isotope being moved to the docks, the perfect place to release the virus from. Cadmus send out a message saying soon all non-humans will die. Supergirl and J'onn head to the docks alone. Lillian hands Lena the keys and, despite Supergirl's protests, she fires the rocket. Supergirl chases it while J'onn battles Henshaw, turning into his White Martian form. Supergirl catches the rocket but Lillian detonates it, releasing a massive cloud of the virus. Supergirl knocks out Henshaw but J'onn and the other aliens are unaffected: Lena switched out the isoptope, rendering the virus inert, and also contacted the police, who arrive to arrest Lillian. However, Henshaw has disappeared.
On an alien spaceship, an underling reports that they have reached the Well of Stars but there is no sign of the Kryptonian pod. Two masked figures tell him to keep searching: Mon-El must be found.
With a living sample of the virus, Eliza is able to not only cure Mon-El but also destroy J'onn's White Martian cells; he appears in his Martian Manhunter form. Mon-El pretends not to remember the kiss and Supergirl also doesn't tell him about it. Maggie visits Alex with pizza and tells her she's realised she needs to be true to herself as well. They kiss.
Another portal appears in Kara's apartment, this time disgourging Barry and Cisco. Kara arrives and, after a round of introductions, Barry reminds her she offered to help him out some time. Kara asks what he needs.
- The scene where Barry and Cisco arrive at Kara's apartment is recycled in episode "", the next part of the crossover.
- This is the first episode of that doesn't feature Kara's opening narration during the title sequence.
- This is also the first episode of the series to not feature CatCo Worldwide Media.
- The Fortress of Solitude displays the same Kryptonian symbols seen in Smallville.
- 2 minutes and 57 seconds before the episode ends, Alex closes a pizza box in its entirety (with the flaps going inside the outer cardboard). However, only a few seconds after a scene cut, the box is shown to have its flaps outside of the outer cardboard even though no one was seen touching it throughout this time.
- At the beginning of the episode, James and Winn argue about who gets to tell Kara that James is the Guardian. Why they're bothering to whisper is a mystery, since they both know Kara is in the vicinity and has superhuman hearing. Even more odd is the fact that Kara doesn't seem to hear them, even though a similar whispered conversation in "" is how she discovered J'onn's real identity.
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