Considerable evidence has emerged through more than a decade of research supporting the neuroprotective and cognition-preserving effects of estrogens. Such basic research coupled with various epidemiological studies led quickly to the assessment of Premarin for the treatment of mild to moderate Alzheimer's disease (AD), initiated by the Alzheimer's Disease Cooperative Study Group and headed by Dr. Leon Thal. While this and subsequent trials with Premarin (Wyeth Research, Monmouth Junction, New Jersey) and PremPro (Wyeth Research), a conjugated equine estrogen preparation plus medoxyprogresterone acetate, have not supported the use of estrogens in treating advanced AD, considerable inferences have been made from these placebo controlled trials of estrogens. Here, we aimed to put these AD trials of estrogens in perspective by considering the potential mechanisms of these potent neuroprotective estrogens, the role of estrogens in other neurodegenerative conditions, such as cerebral ischemia, and based on our current understanding of estrogen neurobiology, offer insight into the design of future clinical trails of estrogens for neuronal protection.