Recent strides in computational biology and high-throughput technologies have generated considerable interest in understanding complex biological systems. The application of these technologies to critical illness and injury offers the potential to define adaptive and maladaptive programs of gene expression induced by infection, shock, trauma, or other inflammatory triggers, and to detect biomarkers and genetic polymorphisms linked to these responses and outcome. A systems biology approach is timely because despite substantial effort, treatment approaches directed at a single mediator or inflammatory pathway have met with little success in altering outcomes of critically ill or injured patients. Highlights from the Fourth National Institute of Health Functional Genomics of Critical Illness and Injury Symposium are described herein, in addition to deliverables for the field identified during panel discussions. Next steps for the community and suggestions for future research are presented.