Resuscitation can exacerbate cellular injury caused by hemorrhagic shock, and the type of fluid used for resuscitation may play an important role in this injury. Unlike some factors in the treatment of combat casualty, the method of resuscitation is under our control. The prevention of cellular injury through wiser resuscitation strategies would be more advantageous than attempting complex immunomodulation after the damage has already occurred. This article summarizes data from a number of studies to illustrate the differential effects of commonly used resuscitation fluids on cellular injury. Our findings show that resuscitation with hypotonic/isotonic crystalloids, including lactated Ringer's (LR) solution, and artificial colloid solutions, elicit severe immune activation and an up-regulation of cellular injury markers. This effect is not seen with plasma, natural colloids (albumin), and fresh whole blood. Hypertonic fluids cause suppression of neutrophil activation and a milder increase in the expression of cell injury markers compared with isotonic fluids. The effect of various resuscitation fluids on core cellular functions such as gene regulation is also summarized in this article. Finally, because of the uniqueness of combat care, a set of new recommendations for initial fluid resuscitation of combat casualties is proposed.