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Anime and Manga
- The Lyrical Nanoha franchise, which began as a mini-scenario included in the Lyrical Toy Box merchandise CD of Triangle Heart 3: Sweet Songs Forever.
- That's very much how Yu-Gi-Oh! became associated with "Duel Monsters", which originally was only one of many games in the manga ("Yu Gi Oh" means "King of Games"). Then Defictionalization of said card game steadily happened, creating a globally known franchise worth billions of dollars in the process.
- The popular 2000 AD series DR and Quinch began as a one-off Future S.hock.
- Spider-Man was treated as a throwaway character and put in the last issue of a failing series because people thought he would be too weird for people to like.
- Superman: A sci-fi comic strip repeatedly pitched by two kids from Cleveland.
Live Action TV
- The Addams Family started as a loosely-connected set of cartoons by Charles Addams in The New Yorker with recurring unnamed character designs. Until the proposal to create a show based on them, Addams had never even thought of them as named individuals.
- The (mercifully) short-lived sitcom Cavemen, based on the "So easy a caveman can do it" series of Geico insurance commercials.
- "Get Happy" began as a short vamp that Harold Arlen improvised while substituting for Fletcher Henderson as rehearsal pianist on the 1929 Broadway musical flop Great Day!. The chorus director, Will Marion Cook, told Arlen to turn it into a popular song, and it indeed became the Breakthrough Hit of his songwriting career.
- Dilbert started out as a unnamed recurring character drawn on the whiteboard of Scott Adams' cubicle while working as an engineer at Pacific Bell.
- Garfield Minus Garfield, which started as a riff of a Memetic Mutation of Garfield (inspired in a thread on the Truth and Beauty Bombs forum about the Garfield Randomizer), and eventually got its own published book by the syndicate, with a commentary essay by Jim Davis.
- The Reduced Shakespeare Company began as a Renaissance Faire act doing a twenty-minute abridgement of Hamlet. Over the better part of a decade, this developed into a full-length theatrical work, The Complete Works of William Shakespeare (abridged).
- Forbidden Broadway began as a cabaret act with a cast of only three, including both Gerard Alessandrini and the pianist (who had to be replaced at the last minute, causing some worry since no piano part had been written out). They could hardly keep up with the costume changes.
- Madballs in Babo Invasion was the sequel to the one-man freeware program Babo Violent 2, which was itself the formalized version of a networking test.
- Geometry Wars: Retro Evolved, which was the Xbox Live Arcade version of an Easter Egg Mini-Game from Project Gotham Racing originally created for testing the input system, and has since become a lucrative franchise in its own right.
- Alien Hominid and Meat Boy, originally just random Flash games on Newgrounds.
- Line Rider, a Flash toy with nothing more than drawing a line for a sled to ride on, which now has its own video game series and social networking website.
- Team Fortress 2, technically the sequel to a 2-or-3 man mod for Quake.
- Not to mention interim games Counter-Strike and Day Of Defeat, which were both Half-Life mods whose small dev teams were bought out by Valve, split into commercial packages, and followed with "Source" versions with a much-improved engine.
- Garry's Mod, the ten dollar commercial version 10 of which has made Garry effectively a millionaire, was originally a quick hack to the leaked Half-Life 2 source code to allow arbitrary rope creation posted on the Something Awful Forums.
- The game that preceded Portal, Narbacular Drop, was a school project at Digi Pen.
- Defense of the Ancients: All-Stars, a WarCraft III map with its own work page, has inspired a top ten single charting theme song, quite a few popular games, among them Demigod, Heroes of Newerth, and League of Legends, and arguably its own genre, and scored its developer a position at Valve Software (they seem to have a thing for Ascended Fanboy developers).
- The idea for Katawa Shoujo began as a one-off joke on an omake page of a manga. Later, some people saw it on an Imageboard and decided to take a serious crack at making a Visual Novel featuring girls with disabilities.
- Kind of a borderline example, but Kerbal Space Program is named after the backstory a couple of the developers made up for a series of model rockets they built and launched together when they were kids.
- Rare's Mr. Pants made his first appearance on their website's Survey page as a hastily doodled placeholder character. He eventually starred in his own Game Boy Advance game.
- Parodius became the most popular of the Gradius series' various spinoffs, but the inspiration for the cheaply-produced MSX game, which preceded the flashier, more popular arcade and console games, seems to have been the joke option of playing as Twinbee in Gradius by plugging cartridges for both games into one MSX.
- Freedom Planet started as a fan game of Sonic the Hedgehog with original characters that took inspiration from the frantic and over the top action games by Treasure. When the team realized how much work was being put into the original characters and unique mechanics, they decided to remake the project as its own IP that was a celebration of the Sega Genesis library with a Sonic-influenced art style that became a successful franchise in its own right with a sequel, widely praised as a unique series that does what Shovel Knight did for the 8 bit games that FP did for Sega platformers.
- Homestar Runner, which now has its own professional video game series and cameos ranging from songs in Guitar Hero to an Easter Egg cartoon in a Macromedia program, started as a children's book made in a college afternoon and put together at Kinko's (see here).
- Red vs. Blue was a one-off trailer a bunch of drunk college friends put together inspired by early Quake Machinima and their obsession with a new game they were playing called Halo: Combat Evolved. When some fans on the very early internet liked it, demand grew for a proper series, which they eventually started in 2003 using rough capture footage from their consoles filming the popular multi-player game of capture the flag. What started as a nonsensical sitcom with Halo characters swearing and lampshading the video game logic eventually grew into a surprisingly complex and ever-growing plot with dozens of developed characters, semi-professional and professional actors, custom CGI animated sequences, an indie rock band to perform the background music, and interconnected epic of war, betrayal, the ethics and morality of artificial intelligence, and comrades in battle while maintaining the witty humor and hilarious banter between Halo characters.
- The Adventures of Dr. McNinja started as Chris Hastings' user name on the Something Awful Forums, which he decided at the last moment to change from Dr. McNugget. He then drew a panel of what said doctor would look like, then used the doctor as the premise of a comic he drew for his art degree.
- Axe Cop is written by a six year old, but drawn by a professional.
- The Nuzlocke Comics originally started out as the sketchings of a Self-Imposed Challenge on a Pokémon run. It utilised stick figures with a storyline that didn't really deviate from the original game for the first season, but, come the next season, there's a noticeable improvement in the artwork and formatting, the storyline becomes much more substantial, and the Pokémon themselves were much better characterised. The challenge itself has also become extremely popular among others, inspiring many other Nuzlocke comics, prose and further creative pursuits in turn.
- Gunnerkrigg Court began as a picture Tom Siddell drew of a pink-haired girl in a drab school uniform. He only chose that subject for his picture because it fit the marker colors he had on hand. These days, Gunnerkrigg Court is Tom's sole source of income.
- Gigi DG publicized Cucumber Quest's humble origins as part of an April Fools' Day gag in 2014. For the day, she revamped the site as Kukobu Quest, featuring her own art and writing from ten years prior.
- morphE began as a weekly World of Darkness game between the four creators. The game spanned for two and a half years and spawned the plot of the comic. The weekly game itself was spawned from a one-shot test game the lead creator ran with a larger pool of friends. There was no intent to expand the one-shot to a full campaign, nor to adapt the outcome. The story just kept growing.
- The first xkcd strips were doodles from Randall Munroe's notebooks.
- The Simpsons, originally a crudely-drawn series of shorts on The Tracey Ullman Show, has gone on for more than 20 seasons and has spawned a merchandising empire, several video games, a movie and ride. The characters themselves were knocked out in the waiting room where Matt Groening was going to meet with executives. Originally, he was going to pitch a show based upon his comic Life in Hell, but he realised at the last minute that he might lose the rights to his own characters, so he quickly sketched a family based upon his own family.
- Trey Parker and Matt Stone's first short "Jesus Vs. Frosty" was done as a student film. Their second short was made on a budget for a Fox network executive... so he could use it as a video Christmas card to send to his friends. After months of underground circulation via bootleg tapes and the Internet, Comedy Central decided to hire them to expand this into South Park.
- The genesis for Phineas and Ferb came one night when Dan Povenmire was at a restaurant and drew a triangle-headed boy and decided to build a show around him. It was sixteen years before the show actually got picked up. The show's villain first appeared in an ad for Middlefield Cheese, an Ohio Amish cheese company in 2004.
- Beavis and Butt-Head was originally just a short on Liquid Television. Likewise Ĉon Flux. Celebrity Deathmatch appeared on the show's Spiritual Successor Cartoon Sushi.
- Mike, Lu & Og grew out of a Russian animated short by Mikhail Aldashin about island natives being introduced to modern conveniences. The execs at Cartoon Network thought it would be a good premise for a series and hired Chuck Swenson (fresh from Klasky-Csupo) as head writer and Mikhail Shindel as producer to develop the series in collaboration with Pilot Studio in Moscow, with Swenson creating the redheaded tomboy to serve as the central character.
- The Boondocks started out as a college newspaper strip before being nationally syndicated and eventually getting a popular television series.
- Wiki Magic.
- Memetic Mutation.
- Yahoo!!, which began in 1994 as a student project on the Stanford University site. As did Google.
- IMDb started as a list of actresses with pretty eyes.
- eBay began because the creator's girlfriend had some Pez dispensers she wanted to sell.
- Ken Thompson and Dennis Ritchie began developing the UNIX operating system on the PDP-7, an underpowered minicomputer. Before development moved to the PDP-11 and added text-processing applications that made Bell Labs take more than an experimental interest in UNIX, it was little more than a set of utility programs supporting a port of Space Travel, a game Thompson had originally written for a more powerful mainframe while working on MULTICS.