Set in a futuristic, alternative history universe in which the Americas were never discovered or colonized by Europeans, Rejects explores how the culture, society and technology of the people may have grown and developed on its own.

In this alternative history, society has become rigidly controlled and stratified into caste systems, science has supplanted religion as the dominant power and genetic manipulation and body augmentation to create superior beings and a warrior caste has become the ultimate goal of the ruling hierarchy. Game play begins with the central character, Tonainan, escaping from a laboratory where genetic modifications and mechanical augmentations were performed on unwilling test subjects in this quest to produce the ultimate warrior.

Underlying questions about what makes us human, what it means to be human, how humanity is defined and how to find a way to fit into and belong in such a stratified society drive the game play experience and ultimately are decided by the players actions and choices over the course of the game, with multiple branching scenarios created or closed off as players make choices about their position and role in the world. Faced with choices, the player can opt to rescue, ignore or kill those around them, influencing how the other characters in the game interact with and view them, as well as ultimately dictating and defining their place in the society.

These questions and difficulties are raised several times over the course of the game, as the genetic modifications made to the central character, Tonainan, and the other test subjects continue to alter their body and physiology even after they escape the labs, gradually replacing their natural body with biomechanical augmentations as the host body struggles to adapt to its changing nature and genetic makeup.

The game centers on, Tonainan Xipil, a member of the lowest caste who, like many of their kind, is born in the lab and used for experimentation and testing in the genetic labs. Escaping the labs and struggling to find a way to exist in a different caste and society from which they grew up in forces them to confront the underlying questions which the game raises and asks the player to experience and empathize with someone who suddenly finds themselves an alien in their own world, confronting racial and social prejudices and discrimination, and struggling to define themselves and their position in the world they have been thrust into, even as their humanity is gradually altered as their body is replaced by biomechanical augmentations.

All while attempting to survive the dedicated team sent to destroy or capture them.