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The bone structure that makes up the majority of the human head is called the skull, with the lower jawbone being a separate structure. As the skull is an internationally-recognized symbol for death, it appears as a symbol in a vast number of games in a great many ways. Actual skulls also tend to make appearances, many supposedly evil or barbaric groups tend to have random skulls impaled on sticks in their territory to show off how tough they are.

A well-known use of skulls is in the Halo series; in addition to serving as the "ball" in the Oddball multiplayer mode (Halo's 'kill the man with the ball' variant), skulls are hidden throughout the campaign levels of Halo 2 and 3, as well as Halo Wars. Each skull has a unique ability that can be triggered on or off from a menu once obtained. Some are to the benefit of the player, such as Halo 2's Envy skull, which gives the Master Chief a cloaking device like his counterpart, the Arbiter. Many others work against the player by making the game more difficult, like the Sickness skull from Halo Wars, which reduces the maximum health of all player units by 50%. Still others don't really grant benefits or disadvantages, instead just adding odd or amusing effects to the game, such as the recurring I Would Have Been Your Daddy skull which adds deliberately silly and humourous dialogue to the game, or Halo 3's Grunt Birthday Party skull, which triggers an explosion of confetti and the sound of cheering children when Grunts are killed with headshots.

Another notable use of skulls was in 50 Cent: Blood on the Sand, in which the protagonist Curtis James Jackson III, alias "50 Cent", was unaware of the location of a specific skull that he believed belonged to him. This mystery was what drove the game's narrative forward, as Jackson and his most trusted associates attempted to determine the skull's whereabouts. This was likely because, unlike most skulls, this particular one was encrusted with gold and jewels, especially diamonds, making it more likely that Mr. Jackson sought the skull for its monetary worth than for its sentimental value.

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