In this article, we review published preclinical and epidemiologic studies that examine progesterone's role in the central nervous system. Its effects on the reproductive and endocrine systems are well known, but a large and growing body of evidence, including a recently published pilot clinical trial, indicates that the hormone also exerts neuroprotective effects on the central nervous system. We now know that it is produced in the brain, for the brain, by neurons and glial cells in the central and peripheral nervous system of both male and female individuals. Laboratories around the world have reported that administering relatively large doses of progesterone during the first few hours to days after injury significantly limits central nervous system damage, reduces loss of neural tissue, and improves functional recovery. Although the research published to date has focused primarily on progesterone's effects on blunt traumatic brain injury, there is evidence that the hormone affords protection from several forms of acute central nervous system injury, including penetrating brain trauma, stroke, anoxic brain injury, and spinal cord injury. Progesterone appears to exert its protective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema, down-regulating the inflammatory cascade, and limiting cellular necrosis and apoptosis. All are plausible mechanisms of neuroprotection.