Ghost in the Shell is a futuristic police thriller dealing with the exploits of Motoko Kusanagi, a member of a covert operations division of the Japanese National Public Safety Commission known as Section 9. The unit specializes in fighting technology-related crimes. She may be named after one of the three Imperial Regalia of Japan and Shirow makes reference to them at the end of the second manga. Although supposedly equal to all other members, Kusanagi fills the leadership role in the team, and is usually referred to as "the Major" due to her past rank in the Japanese Self-Defense Forces. She is capable of superhuman feats, and bionically specialized for her job — her body is almost completely mechanized; only her brain and a segment of her spinal cord remain organic.

The setting of Ghost in the Shell is cyberpunk or postcyberpunk, similar to that of William Gibson's Sprawl trilogy. More than other cyberpunk authors, however, Shirow focuses on the ethical and philosophical ramifications of the widespread merging of humanity and technology, the development of artificial intelligence, and an omnipresent computer network that sets the stage for a reevaluation of human identity and uniqueness. Kusanagi and her colleagues face external threats and also suffer internal conflict over their own natures.

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