Wide variation in outcomes after neurotrauma, despite apparently similar injury severity, suggests that host factors may influence the recovery process. Genetically determined individual differences might be one such factor. The study of the genetic modulation of outcome after neurotrauma is at an early stage. Nevertheless, several important components of the response to neurotrauma can be identified in which genetic differences contribute to variability in outcome. These components include genetic modulators of pre- and postinjury cognitive reserve and behavioral homeostasis, and processes that modulate cytotoxic injury cascades (extent of injury) and injury repair. This work reviews what is known of the role of genetic variation in outcome after neurotrauma with a focus on clinical outcomes after traumatic brain injury. Polymorphisms reported to influence outcome after traumatic brain injury that illustrate important underlying mechanisms are emphasized.