The choices made by the player carry over from episode to episode. The story is affected by both the dialogue choices of the player and their actions during quick time events, which can often lead to, for example, certain characters being killed, or an adverse change in the disposition of a certain character or characters towards protagonist Lee. Unlike many graphic adventure games, The Walking Dead does not emphasize puzzle solving, but instead focuses on story and character development.

Some characters from the original comic book series also make in-game appearances. Kirkman provided oversight for the game's story to ensure it corresponded to the tone of the comic, but allowed Telltale to handle the bulk of the developmental work and story specifics. Lee becomes a protective figure to her to help reunite her with her parents. However, most of the characters are original to this game, which centers on university professor and convicted criminal Lee Everett, who rescues and subsequently takes care of a young girl named Clementine. The game takes place in the same fictional world as the comic, with events occurring shortly after the onset of the zombie apocalypse in Georgia.

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