- Mac – A bright, creative, sensitive and somewhat shy 8-year-old boy and Bloo's creator and best friend who visits Foster's. Mac is often the voice of reason among his friends (especially Bloo) when they're making decisions. However, his good nature tends to make him somewhat naive. He is very attached to Bloo and it is shown in episodes such as "House of Bloos" and "Duchess of Wails" that his biggest fear is never seeing him again because Bloo is what keeps him happy and cheerful and vice versa. Mac becomes extremely high and hyperactive to the point of a rabid mania when he eats sugar. Once in this state, he will become impossible to control, will often become obsessed with seeking any other source of sugar, and if he gets hyperactive enough, will run around naked or in his underwear. He also has a crush on Frankie. Mac and Bloo are the two main protagonists of the series. He is voiced by Sean Marquette.
- Bloo– Mac's 5-year-old imaginary friend and best friend who resembles a simple, domed cylinder. Bloo is often very selfish, egotistic, narcissistic, and occasionally sociopathic as well as having a knack for getting in trouble. Despite all this, he still has a good heart and apologizes for his actions. Bloo loves paddle-balls even though he can't make the ball hit the paddle (though the only time he was able to do it was in the episode "Let Your Hare Down"). His full name is "Blooregard Q. Kazoo". He became increasingly mischievous over the run over the series and can be a show-off. He is the only character to appear in every episode of the series. He is voiced by Keith Ferguson.
- Wilt – A very friendly, very tall, red-colored friend with a stubby left arm, a good heart, and crooked left eye-stalk (which he describes as "wonky"). However, in "Good Wilt Hunting", it is discovered that he was not always this way; he was injured in a fateful accident during a basketball game, leaving his arm crushed and his eye injured. Wilt exhibits consummate good sportsmanship, which he applies to every part of life he can. He is considered the nicest person at Foster's and is known for being excessively polite and apologetic, saying "I'm sorry" in almost every sentence. Wilt has a big heart, is frequently cool and collected, and, only on very rare occasions shows anger at all. His name is an homage to NBA star Wilt Chamberlain. Wilt was shown to be created by Jordan Michaels, a basketball star (and an homage to Michael Jordan). His over-sized basketball shoes always squeak against the floor/ground, no matter what surface he is walking on. According to the episode "A Room with a Feud", between him, Coco and Eduardo, he has been in the house for the longest time. He is voiced by Phil LaMarr.
- Eduardo – A Spanish guardian friend. Eduardo is big, hairy and purple. He has horns, a snout, a pointy demon-like tail and large teeth. Despite his large size, overwhelming strength, and menacing demeanor, Eduardo is docile, timid, lacks confidence, and is very compassionate. He has a toddler-like nature, crying at minor negative occurrences, and being scared of almost everything. However, he can be ferocious if angered or in the circumstance that danger befalls his friends. Eduardo has a fondness for potatoes, dogs, and his cuddly toys. His creator, Nina Valerosa, is now a police officer. He is voiced by Tom Kenny.
- Coco – A bird-airplane-palm tree friend who can only say (or write) her name at various speeds and different emphases. A talent unique to her is her ability to lay colorful, plastic eggs containing a plethora of objects from customized baseball cards to money, at will. Mac, Bloo, Eduardo, Frankie, Wilt, and others usually understand her when she speaks, and often translate for her (though Wilt once admits that he has no idea what she attempts to convey). Despite her helter-skelter appearance and quirky behavior, she can demonstrate a perceived intelligence, principle and kindness. No one knows who her creator is as she was found on an island by two scientists named Adam and Douglass, in reference to the late writer, Douglas Adams. She is voiced by Candi Milo.
- Frankie – Madame Foster's 22-year-old granddaughter, addressed as "Miss Frances" by Mr. Herriman. Frankie is the caregiver at Foster's and helps keep everything in order. In spite of Mr. Herriman's fussiness and fixation with rules and cleanliness, having to take care of everyone and everything in the house, and Bloo's mischief-making (all of which cause her tremendous stress and a bad temper), she is usually very friendly and easy-going. According to her driver's license, she was born on July 25, 1984. She is voiced by Grey DeLisle.
- Mr. Herriman – A gray and white anthropomorphic lop ear rabbit friend imagined by Madame Foster who speaks with a British accent. He wears a tailcoat, white gloves and a top hat, as well as a monocle over his left eye (though it is sometimes seen over his right eye). He is in charge of the house (the "President" of Foster's), is extremely strict about the house rules (or just politeness and order in general), and is often found punishing Bloo for his various misdemeanors. It was revealed in "Busted" that the reason Mr. Herriman is so hard on Bloo is because he feels that, given that he is allowed to stay at Foster's even though he still has an owner, he has already broken one of the main house rules. He is extremely fond of his creator Madame Foster, harboring great respect and loyalty to her, even at her most prominent levels of unabashed pep and energy. Mr. Herriman may be considered unruly Madame Foster's superego. On the other hand, Herriman has a love/hate relationship with Frankie, usually working with her to preserve order at Foster's, yet just as often scolding her for what he perceives (often inaccurately) as "laziness" and "immaturity" from her part (usually stemming from the fact that the amount of work she has to do is too much for her to get all of it done in certain time frames). However, at the end of the 90-minute special "Destination: Imagination", Herriman admits that he was wrong and finally comes to respect and appreciate Frankie. He also has fear of dogs and is easily scared out of his wits whenever he comes across a dog as shown in the episodes "Who Let the Dogs In?", and "Setting a President". He is voiced by Tom Kane.
- Madame Foster – The founder of Foster's and the grandmother of Frankie. Madame Foster is elderly but has childlike boundless energy, and enjoys life to the fullest. Her imaginary friend is Mr. Herriman, whom she imagined when she was a child and never gave up. Like Bloo, Madame Foster occasionally becomes hyperactive and mischievous. However, there are times she's shown to be the wisdom of the house. She is voiced by Candi Milo.
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“The business of a novelist is, in my opinion, to create characters first and foremost, and then to set them in the snarl of the human currents of his time, so that there results an accurate permanent record of a phase of human history.”
—John Dos Passos (18961970)
“It is indeed very possible, that the Persons we laugh at may in the main of their Characters be much wiser Men than our selves; but if they would have us laugh at them, they must fall short of us in those Respects which stir up this Passion.”
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