"Blame!" is a science fiction manga set in a dystopian future where humanity exists within an immense, self-replicating megastructure known as The City. This sprawling, labyrinthine structure has grown beyond human control, expanding endlessly and consuming resources. The City is governed by an artificial intelligence called the Safeguard, which enforces its rules with lethal efficiency. Humans, now a minority, are hunted by the Safeguard and its robotic enforcers, as they are deemed unauthorized inhabitants.

The protagonist, Killy, is a stoic and enigmatic wanderer with a mission to find the Net Terminal Gene, a rare genetic marker that allows humans to access the Netsphere, the digital network controlling The City. The Net Terminal Gene is humanity's only hope to regain control over the Safeguard and halt the unchecked expansion of The City. Killy possesses a powerful Gravitational Beam Emitter, a weapon capable of immense destruction, which he uses to defend himself against the hostile forces within The City.

Throughout the narrative, Killy encounters various groups of humans struggling to survive in the hostile environment. These groups often live in isolated pockets, unaware of the broader state of The City. Killy's journey takes him through vast, desolate landscapes filled with towering structures, abandoned machinery, and relentless enemies. Along the way, he forms alliances with individuals like Cibo, a scientist who aids him in his quest, and other survivors who share his goal of finding the Net Terminal Gene.

The story explores themes of isolation, the consequences of unchecked technological advancement, and the struggle for survival in a world dominated by machines. The narrative is driven by Killy's relentless pursuit of his mission, interspersed with encounters that reveal the fragmented state of humanity and the oppressive nature of The City. The manga's pacing is deliberate, with a focus on atmospheric world-building and action sequences that highlight the dangers of the environment.

"Blame!" is notable for its minimal dialogue and emphasis on visual storytelling, creating a sense of vastness and desolation. The intricate architecture of The City and the mechanical designs of its inhabitants are central to the manga's aesthetic, reinforcing the themes of technological dominance and human insignificance. The series concludes with Killy continuing his search, leaving the ultimate fate of humanity and The City unresolved, emphasizing the ongoing struggle for survival in a world beyond human control.