Inflammation and immunosuppression can cause acute respiratory distress syndrome, multiple organ failure, and sepsis, all of which are lethal posttraumatic complications in trauma patients. Prevention of the inflammation and immunosuppression has been a main focus of trauma researcher for many years. Recently, hypertonic resuscitation has attracted attention as a possible therapeutic approach to counteract such deleterious immune responses in trauma patients. We have begun to understand how hypertonic fluids affect immune cell signaling, and a number of experimental and clinical studies have started to reveal valuable information on the clinical efficacy and the limitations of hypertonic resuscitation fluids. Knowledge of how osmotic cues regulate immune cell function will enable us to fully exploit the clinical potential of hypertonic resuscitation to reduce inflammatory and anergic complications in trauma patients.