Literature suggest that hypertonic saline (HTS) solution with sodium chloride concentration greater than the physiologic 0.9% can be useful in controlling elevated intracranial pressure (ICP) and as a resuscitative agent in multiple settings including traumatic brain injury (TBI). In this review, we discuss HTS mechanisms of action, adverse effects, and current clinical studies. Studies show that HTS administered during the resuscitation of patients with a TBI improves neurological outcome. HTS also has positive effects on elevated ICP from multiple etiologies, and for shock resuscitation. However, a prospective randomized Australian study using an aggressive resuscitation protocol in trauma patients showed no difference in amount of fluids administered during prehospital resuscitation, and no differences in ICP control or neurological outcome. The role of HTS in prehospital resuscitation is yet to be determined. The most important factor in improving outcomes may be prevention of hypotension and preservation of cerebral blood flow. In regards to control of elevated ICP during the inpatient course, HTS appears safe and effective. Although clinicians currently use HTS with some success, significant questions remain as to the dose and manner of HTS infusion. Direct protocol comparisons should be performed to improve and standardize patient care.