First and Foremost, Evil High is intended to be a Comedy. Make sure you broadcast that to your players before they settle on a plan that involves Genocide.
It is in the tradition of gold and silver era comics, with villains intended to be campy, cheesy foils to the heroes who are actually the star of the show. There are costumes, catch phrases, and ample opportunities for quips and monologues. The game is intended to let your players bask in the ridiculousness of being a costumed villain, not as an opportunity to see what would happen if the Villains suddenly stopped being so dumb. Though it's their game too, so they can explore that option as well. Don't interpret this as a need to make foil Heroes on the Super Team... your villains are still young, and still dream of one day finding a Nemesis.
Because of the nature of Evil, it's very easy for the action to get out of hand and for some players to be made uncomfortable. It's hard to know where the comfort zone is for some people, so the best thing to do is draw a firm line in the sand. Evil High is intended to be PG-13. For non-America readers, that means no more than one instance of non-sexual nudity, limited foul language (non-sexual), limited drug and alcohol abuse, and of course, no sex on camera. Violence is A-Okay!
Finally, your villains are the underdogs. In a culture of Good and Evil, with Super Heroes literally walking the streets and presenting the news, villains know they're necessary, but they are not expected to win. The villains are out matched and outclassed at every turn. Make sure your players feel that way, because the world is NOT FAIR. They are going to have to learn that the only way for them to come out on top is to fight dirty. Ultimately, when your players surprise you with something really underhanded, reward them for it.