The episode opens with Kara and her friends celebrating Thanksgiving. While Kara heat visions the turkey, James and Winn argue with Alex over whether to tell Kara about Jimmy's secret. Winn shows up with stuffing (from his mattress) and then immediately tries to suck up to Kara and Alex's mother.
Kara starts Thanksgiving with an annual Danvers family tradition: going around the table and sharing what they're thankful for. Alex shuts down Jimmy's attempt to "come out" as Guardian to Kara so she can come out to her mother and friends....but she gets interrupted by an interdimensional portal mysteriously opening up over their table.
The next morning, J'onn says they need to figure out what Cadmus has planned with Kara's blood. Kara offers to interrogate Lena using her journalism skills and "sneaking"to find out what she knows about her mother, but neither Winn nor Alex are convinced.
Sure enough, Lena tells Kara that she's not close with her mother and always seems to "come up short" in her eyes. After Kara leaves, Lena immediately calls her mother and says they need to talk.
Cyborg Superman plants a device at the unnamed alien bar that releases some sort of gas. Mon-El mistakes him for J'onn and follows him outside, which inadvertently saves his life. After Cyborg Superman beats up Mon-El, Mon-El runs inside to find all the aliens in the bar dead.
J'onn places Mon-El in isolation to keep him from exposing the other aliens. Meanwhile, Alex decides to bring in their mother in order to figure out how Cadmus released a toxin that only targets aliens.
Lena meets Lillian at her office and immediately asks what she's up to. Lillian plays dumb, but Lena says that a reporter (Kara) is sniffing around.
During a game of Monopoly (played with two boards since they're separated by a glass wall), Kara asks Mon-El if he "likes" her, but Mon-El plays dumb and denies it. Mon-El suddenly collapses as he succumbs to whatever virus Cadmus unleashed on the bar.
Eliza stabilizes Mon-El and says that the virus is Kryptonian in origin. Supergirl realizes that Cadmus must have used her blood to break into the Fortress of Solitude. Sure enough, when Supergirl arrives, one of Superman's robots attacks her claiming that she had already intruded on the fortress once before. Supergirl heat visions the robot and then uses the Fortress's computer to look up "Project Medusa". It turns out that Project Medusa was a weaponized virus created by Kara's father to defend Krypton from potential invaders. Medusa can kill any alien, but won't affect Kryptonians.
Kara explains how Project Medusa works to J'onn and Alex, and Eliza explains that Mon-El is still alive because his biology is so close to Kryptonians. Afterwards, Eliza tells Alex that she knows that Alex is gay (Alex talks about Maggie a lot) and says that she loves her no matter what.
Kara admits to J'onn that she's upset that her parents worked on Project Medusa and that their legacy is one of death and destruction. J'onn says that Kara is her parents' legacy but then starts to transform into a White Martian. J'onn warns Kara not to tell anyone until after they've stopped Cadmus. Just then, Alex and Eliza realize that Cadmus needs an experimental isotope from L-Corp in order to weaponize the virus.
Sure enough, Cyborg Superman arrives at Cadmus to take the isotope, but Supergirl shows up in time to fight him. In the subsequent battle, Cyborg Superman tries to kill Lena and injures Maggie, but Supergirl (and a timely interspace portal) manage to keep Cyborg Superman from stealing the isotope.
In the aftermath, J'onn and Winn get Supergirl to talk to Lena about her mother. However, Lena doesn't take the news well and accuses Supergirl of continuing Superman's witchhunt against the Luthors. Supergirl tells Lena that she's not like her mother, but Lena kicks Supergirl out of her office.
Alex patches Maggie up and thanks her for leading her down a path to being more comfortable for who she is.
Mon-El wakes up and admits to Supergirl that Eliza thinks he's dying. Supergirl admits to Mon-El that Medusa is her family's fault, but Mon-El kisses Supergirl after saying that she's absolutely beautiful when she carries the weight of the world on her shoulder.
Lena confronts Lillian about Cadmus, but then gives her the experimental isotope. Lena says that all Lillian had to do was ask for her help and that maybe she didn't know her daughter as well as she thought.
Winn figures out that Cadmus has the virus and is taking it to the port to release Medusa. Supergirl tries to stop J'onn from accompanying her to the port, but J'onn wants to go out a hero instead of an "alien freakshow".
Supergirl and J'onn arrive at the port just as Lena fires the weaponized Medusa in a missile at National City. Supergirl races after the missile while J'onn fights Henshaw. J'onn transforms into a hybrid Green/White Martian and gets the upper hand on Henshaw, but Supergirl fails to stop the missile from exploding. However, when the Medusa virus spreads of National City, neither J'onn nor any of the other aliens die and Lillian realizes that Lena betrayed her by switching out the isotope just as the police arrive.
In the depths of space, a group of aliens are looking for Mon-El and promise to destroy any planet that get in their way.
Meanwhile, Eliza cures Mon-El and says that she uses the Medusa virus to reverse J'onn's White Martian blood poisoning. Kara asks if Mon-El wants to talk about "what happened" (their kiss) but Mon-El claims ignorance about the whole thing so Kara doesn't press any further.
Maggie shows up at Alex's apartment and says that almost dying gave her perspective and starts kissing Alex.0comments
Barry and Cisco finally jump out of the interdimensional portal in Kara's apartment just as Kara walks in. The episode ends with Barry asking Kara's help with a problem and Kara immediately replying who they're going to fight.