Spoiler warning: Plot and/or ending details follow.

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Cecania Greensworthington - The main character of the strip, as most of the stories are either about her or involve her in some way. The sister of Fairbanks, Cecania is outspoken and extremely liberal. Her beliefs cause her to be frequently at odds with her brother, and she testified against him at his murder trial. When she returned home from college after attaining her degree in "TV Horror Show Hosting", she was essentially forced to work at Sore Thumbs in order to pay for her room and board at her mother's home. Cecania is mostly known for her cartoonishly proportioned figure, because of which she is forbidden by the U.S. Supreme Court to wear a bikini in public. When she does, dozens of women commit suicide and several male infants spontaneously go through puberty. She is a vegan and has campaigned for drive-through abortion clinics. Cecania is played by the actress Tyfinni Gwynn.

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Fairbanks Greensworthington - The Proprietor of the Sore Thumbs Video Game Shoppe and Hot Dog Stand, Fairbanks is the outspoken, extremely conservative brother of Cecania. He is a caricature of modern extremist Republicanism. He once drowned two men in soup for 'looking suspicious' (they had beards). The jury acquitted him, mainly because the trial was a week after 9/11. He has been given an award by Senator Joseph Lieberman for his efforts in combating evil. Before Cecania, Harmony and Sawyer arrived, the games in the shop were generally campy in content, such as "Teletubbies: Journey to Nebraska", "Boring Rabbit", "Bounce Ball 2", and "Sandwich: the Game"; since then, the games he stocks have become more mainstream. He was given a medal by the Vice-President of the United States for slaughtering a hive of terrorists while trying to rescue Cecania from the wrong federal facility (even though Coleman was the one who killed most of the terrorists). He is exaggeratedly courteous to blacks, yet openly contemptuous of Asians. As for his personal life, Fairbanks is in a relationship with Harmony (though there are some hints that Fairbanks might be a closet homosexual). He also has a tendency to play video games in the nude. He was originally played by Australian actor Antonio X. Silver, until he was killed by a bull, and is now played by Antonio's mute twin brother, Miguel Silver, Jr., and voiced by Sally Struthers.

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Harmony Nickel - Cecania's bubbly best friend and Fairbanks's love interest, she quit her job as a doctor in the middle of a brain operation to do nothing after finding out that work was hard. Harmony hated being a doctor and only became one because of peer pressure. Harmony loves Fairbanks, but because of her absentminded nature, she at times toys with his emotions or forgets entirely that she is with him. Harmony is played by Sarah Jane Harper, who bore deceased actor Antonio X. Silver's child.

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Sawyer Kaden: The earnest and kind hearted rural beau of Cecania. While serving in Iraq, his penis was cut off by a tribesman on horseback when Sawyer was wandering the desert after a prank by his fellow soldiers. He was initially told that it had disintegrated once it hit the sand (though this is proven to be untrue, since his feet would logically also have combusted), however it is actually being held in Japan as the "beloved flesh Super Mario statue". After returning home, Sawyer started a video game store with the numerous games that were donated to him, though business proved bad until he partnered with Fairbanks. Sawyer is the owner of Coleman the Bear and is devoted to his friends. Though Sawyer's kind nature gives people the impression that he can be easily pushed around, Sawyer has proven that he isn't a man to be taken lightly, He has two tattoos; one of his late mother, the other of Johnny Cash. Sawyer is played by rapper Blingy.

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Coleman the Bear: A dwarf adult blue polar bear. He is Sawyer's pet and best friend, given to him by his commanding officer of his unit after Sawyer's "injury" in Iraq. Coleman is named after the former child actor Gary Coleman. He is usually quite harmless, though Coleman's full ferocity was once unleashed on a swarm of terrorists. Coleman is also known to attack tennis balls and Fairbanks, either because his head is shaped like a tennis ball or because he may just instinctively hate him. Coleman is quite skilled at video games and is often the best player among the Sore Thumbs crew. Coleman is played by the real Gary Coleman, who needs ten hours of makeup a day to make him look like a bear.

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Rondel Mayflower IV: The decrepit, lewd, sexually deviant rival of Fairbanks. He is on good terms with the gang, even though he and his girlfriend Jasmine tried to betray "Fairbanks's Eleven" (the group Fairbanks organized to rescue Cecania) to a terrorist cell (they, in turn, were double-crossed by the terrorists). He is a self-proclaimed "multi-sexual", claiming that bisexuality was "too limiting". He claims to eat a bucket of horse semen every time one of his friends dies, until he is the "last friend standing" (a takeoff of reality television). He is also bald and wears a toupee to cover up the fact. Rondell has made some odd decisions with his money, the most notable example of him having once invested $250,000 into an off-Broadway stage production of War of the Worlds.

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Jasmine: Stone-hearted and sardonic rival of Cecania and girlfriend of Rondel, with whom she has a porn-video contract. Jasmine was originally hired at Sore Thumbs when Cecania left, though she would later defect to Rondel when upon her return. It is strongly hinted she once committed many, many crimes, including infanticide. She and Rondel tried to betray "Fairbanks's Eleven" to a terrorist cell (they, in turn, were double-crossed by the terrorists). Apparently a satanist. Jasmine is incredibly superficial and is proud of the fact she has breast implants.

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Jimmy Peterford: Janitor of Sore Thumbs who is also a Nintendo fan who, several years ago, wrote a letter to Nintendo Power Magazine and successfully predicted the Wii. He has super powers which are telekentic in nature. He previously dated Cecania but broke up with her on order of Fairbanks.

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