The major cause of late death in patients sustaining major trauma relates to the development of progressive organ failure. Recent studies suggest that trauma victims are rendered susceptible to the development of organ failure because antecedent shock/resuscitation renders them susceptible to an exaggerated immune response to late inflammatory stimuli, the so-called two-hit hypothesis. In this article, the rationale underlying the use of a “two-hit” model in trauma research is reviewed and a specific example is cited. Importantly, these models permit investigation aimed at understanding the cellular and molecular mechanisms of disease after shock/resuscitation. Interventions such as antioxidant therapy and hypertonic saline resuscitation have a rational basis for use and have been shown to be effective in a rodent two-hit lung injury model. These studies suggest potential use in the critically ill trauma patient population.