With the development of trauma systems, improved resuscitation, and organ system support, survival after severe injury is common, but is often complicated by nosocomial infection and organ failure. These complications are costly, and can lead to death or disability. Although much is known about the pathophysiology of post-traumatic nosocomial infection and organ failure, findings have been limited by our ability to generate and analyse large amounts of experimental and observational data. However, technological advances in nucleic acid and protein analysis, coupled with increased computational capacity, provide an opportunity to characterise the determinants of and the responses to injury and sepsis on a genome-wide scale. New large-scale collaborative efforts aim to investigate the genome for variation (gene polymorphisms), characterise multiple levels of the biological response to injury (transcriptome and proteome), and relate these to clinical phenotypes. In this article, we summarise recent findings and explore where promising new technologies might have the greatest potential for increasing our knowledge. It will now be important to determine how these recent technological advances can be used and integrated with our existing approaches, to reduce death, disability, and the economic consequences of trauma.