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Angels: Angels in Supernatural are very powerful, the strongest among them, the Archangels, can even take on a whole roomful of Pagan Gods with no difficulty. They can throw people around with their mind, teleport and have a touch that can kill anything. Hell, some of them don't even need to touch to to do it. Humans, demons...and vampires, among others. If you see their true form, your eye's will burn out of their sockets. If you hear their true voice, your head will explode. They carry around angelic swords that again, can kill practically anything. Even vampires. They are a race of warriors and even their medics can end you with barely any effort. And they're almost impossible to kill. You can damage their vessels as much as you want, but the angel inside will survive. If he can get away, he'll also heal all of the damage to the person he's inhabiting too.
And they hate monsters.
Demons: Like Angels, Demons are very hard to kill. Once again, you can trash around their meat-suits, but the demon will live through it. Holy water can hurt them, but not kill them. Damage them enough and they'll just smoke out and find another vessel. Even the low-level demons can toss you around like you're nothing, and they can do it without ever even touching you. Then there's the higher level demons. Those ones not only have telekinesis, but can create fireballs. Some of them know how to use witchcraft and some can force you to do things just by touch. They can drive you into an insatiable hunger, make you mad with lust or force you to lie down and starve to death and you won't even care.
Leviathans: these are basically the Supernatural-verse equivalent of Meyerpires. These things are third oldest beings in the universe (after God and Death, more on him later). They can shapeshift into other people and take on all of their memories. They can kill even angels with just a touch. Not only are they insanely strong, but they are also incredibly hard to kill. They can come back from practically anything. Fire, dismemberment, decapitation, being crushed, they can come back from that. They can be hurt by borax, but it seems that after a while they gain a slight immunity. Their appetite is monstrous, they will eat anyone and everything and I do mean everything. And they hate anything that's not a Leviathan, to the point that they made a chemical that would wipe out all monsters, werewolves, shapeshifters..and vampires. mPowerful Witchcraft can stun thrm, but they snap out of that after a few days. There are only two known sure fire ways to kill them. One is to have a Levaithan eat another Leviathan, so that they can't regenerate and the other...well, that involves four extremley hard to find objects. And that's not an exaggeration, when I say extremley hard, I mean it. First off, you need the bone of a saint and they have to have been saintly all through their life. Any sin committed and the bone is useless. Then you need the blood of three separate beings. The blood of a fallen Angel, the blood from the ruler of fallen humanity, meaning the King of Hell and finally, the blood of an Alpha Monster, as in the very first of their kind. And Alphas are very powerful, moreso than their children. And even if you manage to stab the a leviathan, the backlash will send you and anyone close to you straight to Purgatory, the monster afterlife. And it's impossible to leave.
The Four Horsemen of the Apocalypse: Four of the oldest beings in the Universe, and this four of the most powerful. No only that, but it is literally impossible to kill them. You can weaken them by taking their rings, but it won't kill them and if they give the ring willingly, then they won't lose any power at all. War can make you see whatever he wants you too with just a twist of his ring and you will not be able to tell fantasy from reality. He will set you against the people you love and you won't even know that you're playing into his hands. Then there's Famine, and like the Leviathans, he will eat anything. In fact, his gluttony is even worse. The Leviathans can only eat your body, but Famine? Famine will swallow your soul. Being in his mere presence will drive you mad with greed and gluttony. You will go into a frenzy to get what you want. It doesn't even have to be food, just something that you love or crave. Drugs, sex, whatever, you will be driven to get it. Not even Angels are immune to his effects. Pestilence can create new diseases at will, ones that can kill within seconds, he's only limited by his own twisted imagination. And when he's got that super virus perfected, he'll just brush against you and you will get it. And then there's Death. He may just be the oldest living being in the Universe, he can't even remember anymore. Literally everything is beneath him, humans are less than insects to him, the Archangels are mere children and the only person who's on his level is God...and one day, Death will come for him too. Just being near him can kill you, he can put a man down with just a glance and he can summon natural disasters strong enough to kill millions. And he absolutely hates arrogant people who think that they're better than everyone else.
Pagan Gods: They're a step below Archangels, but they're still incredibly powerful. Some can throw lightning, some can create wild firestorms and some wield weapons that can kill anything short of the Horsemen. Like with the Leviathans, they're incredibly difficult to kill. You usually need stakes made of very specific types of wood, combined with the blood of very specific people or creatures.
Special Children: People who were fed Demon's blood as Children, granting them superhuman powers. Some are telekinetic, some can force you to do things with their mind, some can kill you with a touch and some can summon Demons. By ingesting more Demon blood, their existing powers grow stronger and they even gain new ones. Including thr ability to kill monsters. Even Demons.
The Cambion: The child of a human and a Demon, they're far more powerful than either. He can bend reality to their will and create or destroy whatever they want. Only one exists, a child and he was strong enough to overpower an Angel.
Dragons: Firebrathing shapeshifters how can only be killed by special swords forged with dragon's blood. The swords are incredibly rare and can only be wielded by heroes. So, that puts the Cullens out.
The Colt: This gun, made by Samuel Colt can kill practically anything. Including vampires. There are only five things that it can't kill, one of them being Lucifer himself. The general consensus is that the others are rest of the Archangels, the Horsemen, God, the Leviathans and Eve, the Mother of All Monsters. Everything else, however, is free game. It's even killed one of the King's of Hell, one of the most powerful demons in existence.
Ruby's Demon Killing Knife: Despite the name, the knife kills more than just demons. Angels, vampires and other monsters are all prey to this knife. Only incredibly powerful demons aren't killed immediately by its effects.
Angelic Blades: Same as Ruby's knife, but even more powerful.
Death's Sickle: Death's personal sickle can kill everything. Given how powerful Death is, it's highly likely that it can kill even the Archangels.
Artemis' Bow: The weapon of choice of thr Greek Goddess if the hunt. Like the colt, it can kill almost anything, even things that can regenerate from fatal wounds.