"Blame!" is a science fiction anime series based on the manga by Tsutomu Nihei. Set in a dystopian future, the narrative unfolds within a vast, labyrinthine megastructure known as The City, which has expanded uncontrollably and consumed the Earth. The City is a sprawling, self-replicating construct inhabited by hostile silicon-based lifeforms called Safeguards, which enforce the structure's chaotic order. Humans, now a rare and scattered species, struggle to survive in this hostile environment.

The protagonist, Killy, is a stoic and enigmatic wanderer with a mission to locate the Net Terminal Gene, a genetic marker that allows humans to interface with and control The City's systems. Killy possesses advanced weaponry and regenerative abilities, making him a formidable figure in his quest. His journey brings him into contact with various human enclaves, each struggling to survive under the constant threat of Safeguard attacks. Among these groups is a small settlement led by Cibo, a scientist who becomes a key ally in Killy's mission. Cibo is driven by a desire to understand The City and its origins, and her knowledge proves invaluable in navigating its dangers.

As Killy and Cibo traverse The City, they encounter numerous challenges, including rogue AI constructs, hostile Safeguard units, and the remnants of human civilization. The narrative explores themes of isolation, survival, and the consequences of unchecked technological advancement. The City itself serves as a central antagonist, its vastness and complexity reflecting the overwhelming scale of the challenges faced by its inhabitants.

The story is marked by its atmospheric tone and minimalistic dialogue, emphasizing the desolate and oppressive nature of the setting. Killy's relentless pursuit of the Net Terminal Gene drives the plot forward, with each encounter revealing more about the world and its history. The series blends action, mystery, and existential reflection, creating a compelling narrative that delves into the relationship between humanity and technology in a post-apocalyptic landscape.