Spoilers ahead for Episode 16 of Supergirl Season 3, called "Of Two Minds."
Supergirl Season 3 has pitted Kara and her pals against their most formidable foes in the series to date, and that's saying something after Season 2 introduced the Daxamite threat. The villains of the season are literally known as Worldkillers, and the big bad Reign has brutally beaten Kara on more than one occasion. The only edge the good guys have had in Season 3 has really been that the three Worldkillers haven't been able to work together. Reign was in Sam mode in Lena's lab, Pestilence was unknown, and Purity was the rogue. Unfortunately, "Of Two Minds" brought the three Worldkillers together for the first time, and we now have to wonder if Supergirl may not be able to defeat them.
Kara and the D.E.O. were chasing Pestilence in "Of Two Minds." Birds dropping dead out of the sky at the end of the previous episode were already a big clue that she would be trouble when she turned up, and when people started getting very sick in "Of Two Minds," it quickly became clear that Pestilence needed to be stopped. Winn and Alex got sick, which raised the stakes for everybody at the D.E.O. The good news was that the members of the Legion had the cure to the "blight" written into their DNA, and that could theoretically be used to save the people who were getting sick. The bad news was that their cure was for a later stage of the disease and it could not be tweaked without a sample of Pestilence's DNA.
Given that Blight would go on to take millions of lives in the future, Imra was all about killing Pesilence as soon as possible to prevent that future from ever happening. Kara and Mon-El wanted to give Pestilence a chance for her human side to take back over, arguing that she didn't need to die if there was a chance she could return to herself. In the big confrontation of Kara, Imra, and Mon-El vs. Pestilence, Kara seemed to make progress on turning Pestilence back into the doctor she once was. Her plan might have even worked... if not for the arrival of Purity, who swept Pestilence away and guaranteed that Kara would not be able to talk her down. Two Worldkillers were together.
Two Worldkillers were enough to track down and find Sam, who had been contained by Lena. Sam had a rough ride in "Of Two Minds" due to Lena electrocuting her over and over again, trying to more or less activate her Reign side so she could study Reign. Pestilence and Charity were able to hone in on Sam/Reign's location, with Kara and her pals in pursuit, believing they needed to rescue Lena. They were not expecting to find Lena keeping Sam contained. Sadly, the two Worldkillers were able to bust their sister out of her cage, and Sam was in full Reign mode by the end of the episode. Purity, Pestilence, and Reign are together and ready to live up to their names as Worldkillers.
Kara and the other good guys have struggled to make headway on any of the Worldkillers on their own in Season 3. All three of them together may be unstoppable for the Girl of Steel. There's simply too much power and too many variables in play. The D.E.O. might not have the resources necessary in the time available for Kara to take them down without making some kind of huge sacrifice.
There are a few sacrifices that could theoretically be enough for Supergirl to score a win on the Worldkillers. The biggest and potentially most devastating to Kara might be that she has to move past her stance of no killing. The Worldkillers could be too powerful to be allowed to live; if Kara gets an advantage over one of them at some point, she may have no choice but to strike a killing blow for the greater good.
Another potential sacrifice is her relationship with the Legion of Super-Heroes. She and Imra have already clashed over how to take down the Worldkillers, and Brainiac 5's loyalties are clearly to Imra. Mon-El still has some loyalty to Kara and the D.E.O., but Imra is his wife. Either the Legion or the D.E.O. might do something drastic to take down the Worldkillers, and that something might be so drastic as to dissolve their relationship. Given that the Legion has been quite helpful, the loss of that alliance could be a big deal.
There's also the possibility that Kara or one of her friends will make the ultimate sacrifice to take down the Worldkillers. Admittedly, the show's renewal for Season 4 means that Kara at least won't die and stay dead at the end of Season 4. Others could die, however, and some characters' deaths would undoubtedly change Kara forever. The promo for next week's episode is proof that there's going to be a lot going on, and Kara won't be able to handle everything herself. Take a look!