Estrogen and progesterone are two steroid hormones whose biology has been greatly studied within the confines of reproductive function. As a consequence, the effects of these hormones on the brain have focused primarily on the hypothalamus. Growing evidence, however, forces us to recognize that various extrahypothalamic brain regions, including the cerebral cortex and hippocampus, are equally important targets of these hormones. As such, hormones are involved in numerous aspects of brain function, and elicit effects ranging from the regulation of mood and cognition to the regulation of neuronal survival. While estrogen exerts neuroprotective effects in various experimental models, the potential for progesterone as a protective agent has, until recently, been greatly understudied. Here, we review the data from various laboratories including our own that support the protective role of progesterone and describe the multiplicity of mechanisms by which progesterone elicits these protective effects. Finally, we contrast the neurobiology of progesterone with that of the clinically used progestin, medroxyprogesterone acetate (MPA), and suggest that the "natural" progesterone may be the better choice when considering which progestin to use for future therapeutic/ palliative purposes in CNS-related disorders.