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Arknights takes place in the dystopian world of Terra. Terra may seem initially similar to our Earth, a modern world with a relatively similar level of technology – perhaps slightly more futuristic. However, its inhabitants, the "Ancients", sport animalistic traits.

The world is constantly devastated by Catastrophes, ecological disasters of various sorts, forcing the world's inhabitants to adopt a nomadic life through nomadic cities. Along with the Catastrophes came Originium, a black crystalline mineral left behind in the aftermath of Catastrophes. Originium is widely used by the Terrans as a source of energy and engineering materials, and serves as the catalyst of magic-like powers known as Originium Arts. However, exposure to Originium leads to a "terminal disease" known as Oripathy, which has become a pandemic plaguing all of Terra. Oripathy is not easily transmissible, at least until the death and crystallization of its victims. Nevertheless, those stricken with Oripathy are known as Infected and suffer heavy oppression and marginalization across the entire world.

The game is told from the perspective of Rhodes Island, an international, non-governmental pharmaceutical corporation based in the eponymous nomadic landship, the mission of which is to aid the Infected. Rhodes Island hires many Infected and non-Infected Operators of various skills, trades, and origin; and effectively prove to be much more than a simple laboratory, boasting the paramilitary tactics and firepower of a small private military company. As they are best used to deal with the Infected, R.I. enters conflict with Reunion, a violent non-state actor consisting of radical Infected militants who intend to punish the Terrans for their plight. While Reunion is the game's initial antagonist, it has since expanded to other conflicts, including the succession conflict in Victoria, the rampant capitalism of Kazimierz, encroaching otherworldly threats such as the "gods" of Yan and the Seaborn of Aegir, and the never-ending civil wars in Kazdel, among others. The protagonist of Arknights is an enigmatic individual known only as the Doctor. The Doctor has lost their memory from a long stasis in the mysterious Sarcophagus beneath the nomadic city of Chernobog, Ursus. They are rescued in the game's opening act by Rhodes Island, needing their tactical genius to act as their commander.

Overall, Arknights heavily deals with themes of marginalization, oppression, racism, xenophobia, and geopolitics, and the relative maturity of its storytelling will likely feel familiar to players of Girls' Frontline.