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The series is centered around the exploits of Billy (Richard Steven Horvitz), an idiotic and happy-go-lucky boy; Mandy (Grey DeLisle), a cynical and cold-hearted girl; and Grim (Greg Eagles), a Jamaican-accented Reaper. After Billy and Mandy cheated at a limbo match against Grim (in retaliation for putting the limbo rod too low for them to go under), he is enslaved in a permanently unwanted friendship with the children.[1] Grim is miserable in the first days of his servitude, and even fantasizes about killing them multiple times. However, as the time passes, he gradually adapts to the new life, and even grows to care for Billy and Mandy, if only somewhat. Despite this, he retains a love–hate relationship with the two and desires to eventually break free from his servitude.

Billy and Mandy use Grim's supernatural abilities and powers to venture into supernatural locations or environments, such as the Underworld, or the Netherworld, inhabited by an assortment of grotesque monstrous beasts. The pair also use Grim's enormously strong supernatural abilities or ties with a number of beastly characters to achieve goals or desires for themselves, often with twisted results. Famed fictional monsters including Dracula, the Wolfman, and the bogeyman are also comically depicted in the series.