Ovarian hormones can protect against brain injury, neurodegeneration, and cognitive decline. Most attention has focused on estrogens and accumulating data demonstrate that estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury and from damage due to severe seizures. Although multiple studies demonstrate protection by estrogen, in only a few instances is the issue of how the steroid confers protection known. Here, we first review data evaluating the neuroprotective effects of estrogens, a selective estrogen receptor modulator (SERM), and estrogen receptor alpha- and beta-selective ligands in animal models of focal and global ischemia. Using focal ischemia in ovariectomized ERalphaKO, ERbetaKO, and wild-type mice, we clearly established that the ERalpha subtype is the critical ER mediating neuroprotection in mouse focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke, while in gerbils the two-vessel occlusion model, representing global ischemia, was used. The gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERalpha- and ERbeta-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment protected the dorsal CA1 regions not only when administered before, but also when given 1 h after occlusion. Estrogen rarely is secreted alone and studies of neuroprotection have been less extensive for a second key ovarian hormone progesterone. In the second half of this review, we present data on neuroprotection by estrogen and progesterone in animal model of epilepsy followed by exploration into ovarian steroid effects on neuronal damage in models of multiple sclerosis and traumatic brain injury.