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- Omen III: The Final Conflict. Damien Thorne, the Antichrist, can only be killed by one of the Seven Daggers of Megiddo.
- Hellbound: Subverted, with an attempt to kill the demonic villain with one of the sacred knives that originally bound him inside a coffin proving useless, as he's impervious even to those.
- His Dark Materials has what is a subversion of this. The subtle knife is claimed more than once to be the only weapon capable of killing God (the supposed Big Bad of the series), and its owner is urged to take it to the guy opposing God so he can win the war. Then God turns out to be too old and senile to be the Big Bad, and simply dies of old age.
- Gardner F. Fox's "Niall of the Far Travels" short story "Out of the Eons". Ages ago Adonair, an evil deity from another universe, tried to conquer the world and enslave humanity. The native gods could not destroy him but managed to trap him. At the beginning of the story Niall accidentally frees him. The only way to destroy Adonair is for Niall to drink a special white liquid (that was created by the gods at the same time as they originally trapped Adonair) and trick Adonair into possessing his body.
- Double subverted by Mistborn: the Final Empire. The magic system revolves around metals, of which ten are known to bestow powers. Kelsier spreads rumors of an Eleventh Metal that has the power to defeat the Lord Ruler, but when Vin tries to use it, all it does is show her intangible images of who people used to be. And then the second time she uses it, she realizes that the Lord Ruler isn't who everyone thought he was and uses this knowledge to relieve him of his Immortality Inducer. No Immortal Inertia Ensues.
- The Sword of Shannara has the Big Bad defeated this way, it turns out he had been dead for some time before the book began, reanimated by magic and collective fear.
Live Action TV
- A special Colt gun and bullets, made by Samuel Colt himself, can be used to kill practically anything - but not Lucifer.
- There's a special dagger which is used to kill demons (and the human they possess at the time). Regular daggers don't kill demons, just the host body. It's later revealed to be an ancient demon killing weapon made by the Kurds, but that's all the explanation it gets.
- In one episode the Monster of the Week is a dragon. As Sam & Dean learn, the only way to kill a dragon is with a sword forged with the blood of a dragon. Dean points out the anomaly: "So you need one [sword] to kill one [dragon], but you got to kill one [dragon] to make one [sword]. How does that work out?"
- Buffy the Vampire Slayer had some of these-such as the Hammer of Olaf the Troll, used to whomp Glory down to size, an ancient scythe that kills the otherwise invulnerable Caleb.
- Subverted in the Doctor Who episode "Last of the Time Lords". The episode features Martha Jones spending a year trying to locate a weapon divided into four parts that can defeat the Master, only to reveal at the very end that the Villain-Beating Artifact was a ruse to distract him from Martha's real goal.
- Once Upon a Time has a twist on this trope. The only way to bring down the Big Bad is to steal his dagger, but then you become the villain yourself, if you kill him. You can also control the Dark One with the dagger, which the Duke chose to do and Rumplestiltskin obviously didn't.
- In the first season of Legend of the Seeker, the three Boxes of Orden are treated this way, although it's pointed out that simply killing Darken Rahl will do the trick (although, he's a master swordsman and can Flash Step). Putting the three boxes together allows the person to More Than Mind Control anyone around them, including Rahl himself. However, the power is too seductive and quickly corrupts the user. Richard eventually realizes that the power of Orden must be tempered by a Confession. At the end of the first season, Rahl is defeated by the power of Orden, but not in the way everyone assumed. He tries to interrupt the ritual by thrusting Richard's Sword of Truth between the boxes to split them. The resulting reaction destroys his body, along with the boxes, while also opening a rift into the Underworld.
- The second season features the Stone of Tears, the only artifact capable of defeating the Keeper, sealing him back in the Underworld. In the Grand Finale, the Keeper appears to win by taking the Stone and returning to the Underworld, but Kahlan's tear is turned into another Stone, which is used to defeat the Keeper.
- In most games in the Zelda series Link needs the Master Sword to defeat Ganon. Likewise, the Phantom Sword in Phantom Hourglass is needed to defeat Bellum.
- Also from Zelda, the Silver Arrows (at least in A Link to the Past).
- The Silver Arrows become the Light Arrows in Ocarina of Time, Phantom Hourglass, Twilight Princess, and Spirit Tracks.
- In Link: Faces of Evil, as shown in the page image, Ganon can only be defeated by throwing the Book of Koridai at him.
- Happens again in Zelda: Wand of Gamalon, this time with the titular wand.
- Also from Zelda, the Silver Arrows (at least in A Link to the Past).
- The Three Sacred Treasures in Kid Icarus and Kid Icarus: Uprising are needed to defeat Medusa. Pit later tries to use them to kill Hades in Uprising, but Hades blasts them into nothingness. Pit then went to Dyntos to receive the Great Sacred Treasure, which fared much better, but it also got destroyed, but Pit and Palutena manage to kill Hades by using the Great Sacred Treasure's Wave Motion Gun on him, powered with Palutena's power.
- Sonic the Hedgehog games have traditionally ended with Sonic (and sometimes whatever ally he has at the time) using the Chaos Emeralds to go super, since the Final Boss would be too powerful otherwise, and much of the time, they're out in space or otherwise flying, which Sonic can't do on his own. Though, he does later prove he can take down Perfect Chaos, the former Final Boss of Sonic Adventure, in Sonic Generations without the Chaos Emeralds, or at least he has grown much in strength since then.
- Sonic and the Secret Rings had the World Rings, which Sonic uses to turn into Darkspine Sonic and defeat Alf Layla wa-Layla, the One-Winged Angel form of Erazor Djinn. In Sonic and the Black Knight, this happens in two forms: first using the Sacred Swords (Lancelot's Arondight, Gawain's Galatine, Percival's Laevatein, and Sonic's own Caliburn) in order to defeat King Arthur, and then using Excalibur, a sword formed from all four swords combined, to become Excalibur Sonic and defeat the Dark Queen, the One-Winged Angel form of Merlina the Wizard.
- Sonic Rush Series had Blaze using the Sol Emeralds to become Burning Blaze, while Sonic used the Chaos Emeralds to become Super Sonic as usual.
- In Neverwinter Nights 2, The Silver Sword of Gith is the only weapon capable of harming the King of Shadows. Unfortunately, it was broken into several shards the last time it was used, and your character isn't the only person interested in collecting them.
- One quest in Arcanum: Of Steamworks & Magick Obscura requires you to find a specific dagger so that you can kill a wizard whose soul is bound to a demon. Killing the wizard with any other weapon will release the demon into the world. Also, the final boss can only be killed with one of two items, the Vendigroth Device or Kryggird's Falchion.
- In the God of War series, the power contained within Pandora's Box is the only thing capable of killing a god. Kratos spends the first game trying to find and open the box so that he can defeat Ares. In God of War III he needs to open it again in order to defeat Zeus... or so he's led to believe, as the box is, in fact, still empty since the last time he opened it.
- The original version of Doom 3 requires that the player use the Soul Cube (which they get early on) to take care of the Cyberdemon, the final boss of the game. The other, smaller demons, however, weren't limited to such a weakness, not to mention the fact that the Soul Cube uses the souls of fallen enemies to power it up enough to take on the Cyberdemon. This is subverted both in later patches of single-player mode and in co-op mode.
- Warcraft III: Not a specific weapon, but a damage type. Divine armor is only affected by Chaos damage, which is mostly reserved for the Legions of Hell or extremely strong monsters. In order to defeat the otherwise invulnerable demigod Cenarius, Grom Hellscream's orcs reactivate a demonic pact, allowing them to defeat him (by giving them Chaos damage).
- Also, Illidan devours the Skull of Guldan which the Legion was using to spread corruption throughout the Night Elves' forests. This transforms him into a half-demon, and gives him the ability to defeat the demon Tichondrius.
- Prince Arthas is told that, in order to defeat the dreadlord Mal'Ganis, he must find the legendary sword called Frostmourne. After finding it, Arthas confronts Mal'Ganis. Mal'Ganis laughs and tells him that he fell right into their trap, as the sword has now consumed Arthas's soul. However, while that is true, Arthas's true master is the Lich King, who appears to serve the Burning Legion but has his own goals. He commands Arthas to slay Mal'Ganis, which he does.
- In Chrono Cross, you can kill the Time Devourer just using force, but using that method, it's able to come back. The only way to kill it permanently is using the Chrono Cross.
- Distilled down to its essence in Grow RPG: in addition to the best sword and armor, you've got to have the special blue orb that knocks the Big Bad's health meter down to where you can actually trade hits with it. (It may not be possible to reach the Big Bad without it, though.)
- The sword Dragonslayer in Breath of Fire IV is the only means of killing a dragon (which are beings akin to gods in the game's setting). It is used in this capacity twice; in a failed attempt to assassinate Fou-Lu by Soniel, and to Mercy Kill Elina when the extent of Yuna's experiments on her become known.
- In Baldur's Gate II the Unseeing Eye is advertised this way, and you're told that you'll require a special rod of destruction to be able to defeat him. In actuality it's much easier (though less profitable) to simply start killing his followers until he appears, as he's a fairly standard mage with a few more hit points than normal, and less dangerous than the beholders you'll need to kill to retrieve the rod.
- In Samurai Jack, the title character's sword is the only weapon capable of taking out Aku, since the sword was forged out of goodness.
- The Elements of Harmony in My Little Pony: Friendship Is Magic, wielded by the "mane six", were needed to take down two villains: Nightmare Moon and Discord. Celestia suggested that they use it on Queen Chrysalis, but they never get the chance to use it due to being captured before that can happen. In the premiere of Season 4, the Mane Six return the Elements to the Tree of Harmony to save it, meaning they no longer have any villain beating artifacts.
- At the finale of season 4, there seems to be a new one: the box spawned by the tree contains a new power for them.
- The Season 3 premiere introduces the Crystal Heart, seemingly the foreign equivalent to the Equestria-based Elements. Sorcerous Overlord King Sombra hid it instead of just destroying it, because: (1) he implicitly wanted to convert it into an Artifact of Doom for himself, and (2) he explicitly needed it to shield the Crystal Empire from the Frozen North's extreme weather.
- In Adventure Time, Billy's gauntlet has the power to seal the Lich. The Lich destroys it before Finn can use it against him, and Finn ends up using the Power Of Liking Someone A Lot to destroy his physical form.
- In Scooby-Doo! Mystery Incorporated, the gang eventually learn that they need to find the Heart of the Jaguar to destroy the evil Annuaki sealed in the Crystal Sarcophagus. In the final episode, it's subverted in a Magic Feather way. The true "Heart of the Jaguar" isn't the crystal spearhead (which was shattered earlier), it's The Power of Friendship that binds the gang together. The gang work together to defeat the entity, with Scooby using the spearshaft to shatter the sarcophagus.