Retribution is set in the universe fans know well from the video game and novel series—one in which humanity has explored the very farthest reaches of the universe, only to discover the ruthless Reapers, a race bent on extinguishing all organic life. One man is bent on discovering the Reapers' secrets, the mysterious Illusive Man, the leader of a pro-human, black ops group, Cerberus. And he's devised the perfect plan: implant a human subject with Reaper technology in order to study the enemy.
He also has the perfect test subject—Paul Grayson, an ex-Cerberus operative. Grayson betrayed Cerberus in order to save his daughter. So when Grayson is kidnapped and made the subject of Cerberus' evil experiments, the Illusive Man will finally have his revenge...
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Eli melko selkeetä on, että pelaajan päätöksestä lopussa huolimatta, Cerberuksella on käsissään Reaper-techiä, jota se alkaa kokeilemaan ihmisiin. Fanit ovat kirjan julkistuksesta lähtien spekuloineet, että onko Shepardin kohtalona tulla Sarenin kaltaiseksi puolirobotiksi ihmiskunnan puolesta. Puistattava ajatus, mutta jotain epätoivoista hienouttakin siinä on.