The Poseidon saga of Saint Seiya had the heroes go and destroy 7 giant pillars below each ocean, to be able to destroy an even larger pillar in which Saori was trapped. Each pillar had a guardian of course, and 5 of those guards ended up dead.
Villainous example in D.Gray-Man, where the Millennium Earl wants to destroy all Innocence. This may be made easier by the fact that one of the 109 Innocences is the Heart, which will destroy all the rest if it is destroyed.
A Downplaying of this trope is the central plot of Gash Bell. Although you don't technically kill your enemies (you just send them back to the alternate dimension where they came from), the effect is the same.
Rave Master uses this, where the group's quest is to destroy the Dark Bring (Shadow Stones).
In Bakuman。, the main characters show their editor, Hattori, a story idea for a series about a world infested with demon dragons that has a sword with many demon dragons sealed inside. Every time one is killed, another emerges from the sword, and if the hero kills all of them without losing the sword to them, peace will be restored. Mashiro finds the story to be old-fashioned and stereotypical, but thinks it's worth showing to Hattori, and Hattori tells them they'll have to come up with a better idea than that if they want to go mainstream.
Villainous example in Naruto- the Akatsuki are seeking to collect and extract all nine tailed beasts in order to form the original ten tailed beast. The extraction process is fatal to the Jinchuriki.
Kurapika in Hunter × Hunter- is out for revenge with a double shopping list: Kill all the Genei Ryoudan that killed all his tribe, and retrieve the eyes they stole from his tribe's people's corpse.
In the X-Men novel series Time's Arrow, our heroes have to take out the Time Arrows that threaten to delete parallel universes a la DC's Crisis on Infinite Earths. Or at least that's what it's supposed to look like at first.
The premise of Scott Pilgrim, albeit a quirky spin on it in terms of the trope and its execution. In order to date the (literal) girl of his dreams, Scott has to defeat her League of Evil Exes. In this case, "defeat" roughly translates to "inflict bodily harm until they explode in a shower of coins".
In Perfection Is Overrated, the goal of the SUEs is to kill all the Himes, and the one who succeeds will seemingly be rewarded with the power to change the world as she sees fit. In reality, she will be possessed by the Usurper.
In Kind Hearts and Coronets, Louis Mazzini, black sheep member of the D'Ascoyne family, kills off six members of the family in order to become the Duke of D'Ascoyne. Bonus — the six D'Ascoynes (plus two more who save Louis the trouble by dying on their own initiative) are all played by Alec Guiness!
Because Skynet has little information about Sarah Connor's 1980s whereabouts other than that she lived in Los Angeles at the time, as soon as he arrives The Terminator simply looks up "Sarah Connor" in the phone book and goes down the list killing anyone with that name - it even gets him labelled the "phone book killer" by the media.
The Dangerous Days of Daniel X - The whole premise of the book series. Danny essentially has a big wanted list of alien criminals on Earth, and surprise surprise the one that killed his parents is number one on the list. The entire series basically revolves around him killing off or capturing the aliens on the list one by one, making his way to the one who killed his parents.
In The Wheel of Time, although not necessarily required, Rand & Co. are killing off the 13 Forsaken one by one since they are trying to release the Dark One.
In A Madness Of Angels, each section of the book consists of Matthew tracking down and killing or defeating the head of one of the subsidiaries of the Tower, until the climactic scene where he fights the head of the Tower itself. More or less.
In the original novel Dracula, the vampire hunters have to track down and destroy the 50 boxes of earth Dracula transported to London from Transylvania and scattered throughout the city so that he will have no safe haven to go to when the sun rises or to change his shape.
“I don’t fault you for not seeing the big picture, Captain. After what was done to me, it took me a while to understand what I needed to do so that I could be whole again. But when I meet the Prophets, they’ll see inside me, just as they did with your Emissary. They’ll understand what I need to get my life back. And I’ll use the Soul Key to find every other Kira that has laid claim to a piece of my soul”.
In The Hunger Games, 24 children are pitted into an arena to fight to the death. Throughout the book, the main character frequently recounts how many children are left to compete with.
Kamen Rider Decade has the titular hero being told that, in order to avert the collapse of The Multiverse, he has to travel to the realities of the last nine Heisei Kamen Rider series and kill all of the heroes. He refuses, of course, and helps the Riders. It turns out that the collapse proceeded apace, accelerated by the villains but inevitable with or without them. When Decade was provoked into going to his Superpowered Evil Side, slaughtering all Riders as Decade Fury, the worlds, no longer being forced together by the Riders' powers, were all restored to their original states - including the slain Riders. It turned out plan A was the right one and Everybody Lives in the end.
The nineties show Brimstone features a policeman brought back from hell (it's complicated) by the devil to return a number of escapees to hell the hard way (killing them, though the vast majority are only vulnerable in the eyes.)
The entire premise of Arrow; Oliver even has a literal list to work from and cross names off of.
In FASA's Earthdawn, in order to kill a Horror one must first kill its physical body, then travel to the astral plane and kill its astral body.
Not quite the case; depending on the Horror, you might only need to be a Badass Normal fighter and kill it physically like any other critter. Other Horrors on the weaker end of things only exist on the astral plane, and therefore can only be killed there. Only the REALLY BAD Horrors (i.e.: the more powerful Named ones that will quite happily kill your party with ease if you bump into one of them) must indeed be killed on both planes of existence to be declared Deader than Dead.
The ultimate goal of the Necrons in Warhammer 40,000: by exterminating all life (including bacteria), they close off the Warp (an alternate dimension essentially made of emotion), pretty much the only power that can stop them. Fortunately, most of the Necrons are still dormant.
Liliana Vess from Magic: The Gathering made a Deal with the Devil - well, several devils - for eternal youth and beauty and power and all that good stuff, in exchange for which the demons would get her soul. Then she decided that, while the youth and beauty and power were all well and good, she'd also like to keep her soul. Cue Liliana going and hunting down each of the demons to permanently terminate the contract. One of the demons, Griselbrand, was trapped in a magical vault on the plane of Innistrad. Good thing for the people of Innistrad that when Liliana shattered the vault, she also freed their archangel Avacyn...
The members of the United Assassins Association in No More Heroes. As the main character, Travis has to murder the top ten ranked assassins in the nation, one by one, to rise through the ranks and gain the top spot for himself.
Most of the NES and SNES Mega Man games have the titular character hunting down Robot Masters to take their powers and eventually fight their evil master, Dr. Wily himself.
In Sonic Adventure 1, E-102 Gamma's story following his rebellion against Robotnik is to find and "liberate" his fellow E-100 series robots. "Liberate" in quotes because he destroys them and frees the captured animal powering them. The last one to die is, of course, Gamma himself.
Halfway through Seiken Densetsu 3, the eight God Beasts are released into the world, and the heroes are forced to go out and slay each one of them. Of course, that just plays straight into the villain's plan.
The six dragons in Chrono Cross. Well, you can get by without beating the Black Dragon, but that's only if you fail to do it the right way.
To some extent, the four sentinels in Wild AR Ms 5. They're guarding four towers that have to be destroyed before you can fight the Big Bad Volsung.
Though you don't actually kill them, the whole point of the main series Pokémon games is to defeat the Gym Leaders in each city by knocking out their Pokémon, so you can defeat the Elite Four and subsequently, the regional Champion. The Frontier Brains can qualify as Bonus Bosses in regards to this goal, though.
The Desert Treasure Quest in RuneScape involves running around the whole continent and defeating four guardians who hold four diamonds you need to access an ancient pyramid, where the eponymous treasure is located.
The "Gnomes Are Evil!" sidequest in Fable III. Due to a magical spell gone wrong, 50 garden gnomes were given sentience and then teleported all over Albion. You have to hunt them down and shoot them, which transports them back to their owner. Fortunately the gnomes are foul-mouthed, annoying little jerks.
Fable II is similar, with 50 foul-mouthed stone gargoyles who you must shoot.
The Assassin's Creed series basically embodies this trope. From the main plot of all three games revolving around assassinating a group of villains, to the optional sidequest of killing the 60 Templar Knights in the 1st game.
To a greater extent, in Majora's Mask, you have to destroy the guardians of all four Termina temples to free the Giants.
Twilight Princess has 60 Poe souls for you to collect in a side quest by killing Poes. They're pretty much everywhere and some are only visible at night. Happy ghost hunting!
The goal of Crackdown is simply to kill about 20 different gang bosses, and a skilled player could simply charge off and get to work immediately upon starting a new game. Of course, leveling up your skills and finding new weapons will help out a lot.
Going for 100% Completion in Grand Theft Auto IV? Among other things, you'll need to kill all ten most wanted criminals on each island (Broker/Dukes, Algonquin, Alderney), and you'll also need to kill all two hundred pigeons scattered across Liberty City.
Grand Theft Auto V ups the ante with the final mission. What do you do when you are blackmailed by two of your worst enemies to kill one of your companions, and you will die if you don't comply? Why, you simply have to Take a Third Option and kill everyone who opposes your band.
Pretty much the main objective of Arena mode in Team Fortress 2, your team's goal is to kill everyone on the opposing team while they try to do the same to you. Whichever team still has at least one player standing at the end wins.
In Dark Souls, the player needs to collect the remaining Lord Souls to open the way to the First Flame. How do you get the Lord Souls? By killing the Bad Assgods you see in the Action Prologue.
S4 League's Chaser mode. Each round, one player is randomly designated as the Chaser and has to kill all of the other players, who have to defend themselves until the time runs out. The Chaser gets bonus points for killing whoever has the most points of anyone alive, and gains extra points if they kill every opponent which also deprives the victims of any points (15 if alive when time runs out, 5 if dead but other players survive).
This is pretty much the goal of every Monster Hunter game, since the majority of quests ask you to kill a certain monster, which you can carve afterwards to get useful parts to build armors and weapons with. There are occasions where you're asked to capture a monster alive, but it's a rarer occurrence.
Most individual missions in X Com Enemy Unknown are played this way: To succeed, you have to kill or disable every alien in the zone. There are a couple of Escort Missions where you just have to get one character to the exit area (possibly with a couple of tasks on the way), and to win the final mission and the game, you just need to kill one particular alien (though it's hard to get to him without killing almost every other alien on his ship).
The Holders Series - of course, it's a tossup as to whether the results of bringing them together or preventing them coming together are worse, and if they are all destroyed they will "unite in the destroyed state", so it's rather a no-win situation.
Antibiotics and pesticides: The danger of bacteria and pests developing immunity to chemicals make it important that these chemicals be used sparingly, but when they are used, they should be used in sufficient amounts and for sufficient durations that the pests are truly wiped out.
Vaccines: Same as above, the ultimate finish line would be the complete eradication of a/all disease. Still a long way to go, but we're making progress.