The positive efficacy of estrogen replacement therapy (ERT) in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD) is a matter of intense debate among clinicians and neuroscientists. The experimental and preliminary clinical evidence supporting the use of ERT are based on epidemiological data and on the study of the effect of estrogens on several aspects of brain homeostasis, including the modulation of neurotransmitters and vascular changes. In spite of numerous data available the mechanisms underlying the putative estrogen effects in neurodegenerative diseases are largely unknown. The aim of this paper is to discuss and elaborate on some of the hypotheses and controversial findings currently present in this field.