Despite decades of laboratory research and clinical trials, a safe and effective 
treatment for traumatic brain injury has yet to reach clinical practice. The 
failure is due in part to the prevalence of a reductionist philosophy and 
research praxis that targets a single receptor mechanism, gene, or brain locus. 
This approach fails to account for the fact that traumatic brain injury is a 
very complex disease caused by a cascade of systemic toxic events in the brain 
and throughout the body. Attention is now turning to pleiotropic drugs that act 
on multiple genomic, proteomic, and metabolic pathways to enhance morphological 
and functional outcomes after brain injury. Of the agents now in clinical trial, 
the neurosteroid progesterone appears to hold considerable promise. Many still 
assume that progesterone is "just a female hormone" with limited, if any, 
neuroprotective properties, but this view is outdated. This review will survey 
the evidence that progesterone has salient pleiotropic properties as a 
neuroprotective agent in a variety of central nervous system injury models. This 
article is part of a Special Issue entitled: Neuroactive Steroids: Focus on 
Human Brain.