Increased intracranial pressure after neurologic injury is a clinical challenge that often requires administration of osmotic agents. The most common osmotic agent used for treatment has been mannitol; however, interest has been renewed in using hypertonic saline after neurologic injury, since it is not associated with hypovolemia. The types of procedures or injury for which hypertonic saline has been used are vast, from elective craniotomy for tumor resection to stroke and traumatic brain injury. Unfortunately, there is a paucity of well-controlled clinical trials that provide evidence for the best concentration, administration approach, and length of therapy with hypertonic saline. The bulk of the data exists for traumatic brain injury, although most of these data are from observational and retrospective analyses, which do not allow for an evaluation of the impact of hypertonic saline on clinical outcomes. Nonetheless, both animal and clinical data suggest that patients with traumatic brain injury and those with stroke may benefit from hypertonic saline therapy. Since hypertonic saline has a high risk of injury with inappropriate administration and is considered a "high-alert" drug, safety issues surrounding its dispensing and administration must be considered. Randomized outcome trials comparing mannitol with hypertonic saline in various subpopulations of neurologic injury would add valuable information to the literature and provide a basis for establishment of best clinical practices.