Brainiac

At first glance, Brainiac seems like the kind of villain best suited for the big screen. While that would certainly do the character justice, Smallville proved that he can be handled well on television, and he could be just the kind of big threat that the Supergirl TV series needs. There have been several versions of Brainiac in the comics, one of the most popular being that he's a self-aware artificial intelligence from the planet Krypton. Seeing as Superman himself will be largely absent from Supergirl, introducing another Kryptonian character like Brainiac would be a great way to play around with Kara's origin. Add the bottled city of Kandor into the mix, and you've got yourself one compelling story about a girl who grew up on Krypton and has access to one final piece of her homeworld - she just has to get through Brainiac first. A future version of Brainiac, Brainiac 5, even strikes up a relationship with Supergirl, something that the series could allude to.