It is well known that estrogen can have undesired stimulatory effects on the breast and uterus, which raises concern for a potential increased risk of developing breast and uterine cancers and increased risk for stroke. These potential limitations have kindled interest in the development and therapeutic use of nonsteroidal SERMs. A number of studies have now appeared in the literature demonstrating neuroprotective actions of nonsteroidal SERMs. For instance, pretreatment with the raloxifene analogue LY353381.HCl, a raloxifene analogue, protected the caudate-putamen region of the brain of OVX female rats in an ischemia-reperfusion model of ischemic stroke [39]. LY353381.HCl did not affect cerebral blood flow, suggesting a potential direct neuroprotective effect of this SERM in the brain. Additionally, several studies have shown that the SERM, tamoxifen also significantly reduces infarct size in both transient and permanent occlusion/reperfusion models of cerebral ischemia [40–43]. Like the raloxifene analogue, the protective effect of tamoxifen was independent of cerebral blood flow changes, indicating a potential direct neuroprotective effect of this SERM in the brain. Interestingly, intravenous injection of tamoxifen was protective even up to three hours after cerebral ischemia [43]. These studies suggest that development of nonsteroidal SERMs that specifically target the brain for neuroprotection may be possible [44], and should be a focus for future studies in the area.