Estrogens have profound effects in the brains of all mammalian species studied, including humans. Classical investigations in the female of the species focused on central regulation of ovulation and reproductive behaviours, but mounting evidence demonstrates potent estrogenic influences on diverse brain functions, including learning, memory, mood and neurodegenerative processes1. Consequently, recent years have seen an explosion in the scientific literature documenting the neurotrophic, neuroprotective and psychoprotective actions of estrogens, indicating important therapeutic potential for brain-active estrogenic compounds. The majority of these studies have been performed in females, where the ovaries are the main source of circulating estrogens. However, it is now recognised that that estrogens and estrogen receptors also play important roles in the physiological control of many tissues and organs, including the brain, of the male of the species. This understanding came with the realization that estrogens can be synthesized locally from steroid precursors, including circulating testosterone, by aromatase enzymes, which are found in neurons and glial cells of the brain. Furthermore, estrogen receptors are widely distributed in the brains of both sexes. It is, therefore, tempting to speculate that estrogen-based therapy holds potential for the treatment of brain disorders that affect both males and females. Recent experimental investigations in males would, however, caution against extrapolation of research findings in one sex to another, because estrogens can have different, even opposite effects, as well as similar effects, in males compared with females, depending on the situation. For example, our own and other studies using rodent models of Parkinson’s disease (PD), demonstrate that ovarian factors, specifically estradiol, can protect females against the loss of dopamine in the striatum, which is pathognomonic of PD2. This supports the view that the notable sex differences seen in both clinical and experimental PD, where females fare better than males, may be attributable to the female physiological levels of circulating estradiol. In contrast, in male rats we have demonstrated that physiological levels of estradiol are not protective, and may even exacerbate the loss of striatal dopamine in experimental PD. Sex dimorphisms have also been demonstrated for estrogen’s ability to influence synaptic plasticity, neurotransmission and cognition1. Current evidence points to fundamental sex differences in the organization of brain circuitry in early development as a major factor that underpins sexually dimorphic responses of the brain, and the actions of estradiol in particular. It is now widely recognised that there are notable sex differences in the incidence and manifestations of virtually all brain disorders, including neurodegenerative diseases (PD, Alzheimer’s disease), addictive behaviours, anxiety and depression. A better understanding of the basis of sex differences in brain physiology and hormonal actions is, therefore, vital if we are to unravel the nature and origins of sex-specific pathological conditions and to optimise treatments for both women and men.