Although oestradiol activates multiple neuroprotec¬tive signalling pathways, several studies have shown that the inhibition of individual pathways can dramatically reduce or abolish neuroprotection. This may indicate that certain signalling pathways are more relevant than others depending on the type of neurodegenerative con¬dition. Indeed, the signalling of some ERs seems to be more relevant than that of other ERs, depending on the pathological model and the readout examined. However, we favour the idea that the global homeostatic neuro¬protective action of oestradiol may be achieved only by the coordinated action of multiple mechanisms, all of them indispensable. Thus, inhibition of an individual mechanism may compromise the final neuroprotective outcome. In this regard, an important gap in our knowl¬edge is how these multiple mechanisms are coordinated in time and among the different brain cells. The limited evidence available indicates that both neurons and glial cells participate in the protective actions of the hormone in vivo. However, it is unclear how neuron-initiated and glia-initiated neuroprotective signalling are coordinated. The potential role of endothelial cells in the neuropro¬tective actions of oestradiol, in particular after stroke19, also needs further investigation.