Estrogen exerts neurotrophic and neuroprotective activity as suggested by both in vitro and in vivo evidence. Expression of estrogen receptors has been demonstrated in neurons and also in glial cells. Glia, and in particular astrocytes, represent a target for estrogen and contribute to the neuroprotective effect of the steroid hormone. Particular emphasis is given here to the role of astrocytes in mediating some of the protective effects of estrogen in models of neuronal damage. Estrogen receptors are up-regulated in different brain areas during neurodegeneration, a phenomenon that may potentiate neuroprotective mechanisms, and estrogen appears effective in modulating the uptake of the excitotoxin glutamate. In addition, following neuronal insults, astrocytes may represent a source of estrogen through over-expression of the estrogen-synthesizing enzyme, aromatase. The contribution of astrocytes as a source of growth factors is also discussed in terms of the neuroprotection obtained in different in vitro models of neurodegenerative conditions. Drug Dev. Res. 66:126–135, 2006. © 2006 Wiley-Liss, Inc.