In parallel with the advances in our knowledge of the roles of brain-derived oestradiol in neural function and neuroprotection, considerable recent progress has been made in establishing the underlying molecular mecha¬nisms. In particular, it has been discovered that oestro¬gen receptors (ERs), either associated with or embedded in the plasma membrane, or located in the cytoplasm or the nucleus, coordinate multiple neuroprotective signal¬ling cascades. These include those activated directly by ERs and those activated by the interaction of ERs with the receptors for other neuroprotective factors. Here, we also review these recent discoveries, which represent an essential advance in our understanding of the role of these receptors in the brain and have opened the possibility of using specific ER ligands to promote neuroprotection.