EPO has been shown to provide neurotrophic [Konishi 1993] and angiogenic effects [Yamaji 1996], and it has the potential for neural regeneration [Siren 2001]. These effects are dose-dependent and unrelated to the nerve growth factor (NGF) [Konoshi Y 1993]. The distributions of EPO and EPO-R correspond to the sequence of histopathological changes of cerebral ischemia/infarction. In acute hypoxia (cardiac arrest), strong immunoreactivity of EPO can be found in vascular endothelium, while the EPOR is expressed strongly in neurons [Siren 2001]. After cerebral ischemia, EPO plays an important role in angiogenesis and glial reaction. EPO immunoreactivity appears in the endothelium, intravascular inflammatory cells and neurons of the penumbra. Also EPO-R is expressed in neurons, astrocytes and endothelial cells [Bernaudin 1999, Siren 2001]. Because the expression of EPO-R precedes the up-regulation of EPO synthesis [Bernaudin 1999], the sensitivity to EPO increases [Chin 2000]. In contrast, these changes are not detectable in non-ischemic cortex [Bernaudin 1999], indicating an increased potential for EPO to act where neurons are at risk [Siren 2001]. By protecting endothelial cells from apoptosis, EPO can increase cerebral blood flow, improve microcirculation of the penumbra, and improve tissue oxygenation by angiogenesis, thus significantly reduce the infarct volume [Bernaudin 1999, Siren 2001]. This angiogenesis corresponds to the finding that under hypoxic conditions such as exposure to high altitudes, the brain increases the mean microvascular density [Lamanna JC 1992]. In old infarcts, EPO and EPO-R are strongly expressed in reactive astrocytes. Thus the EPO system may participate in the repair process [Siren 2001]. The persistent up-regulation of EPO production by astrocytes after stroke also provides rapidly available sources of EPO to make neurons more tolerate ischemia [Siren 2001]. These endogenous neuroprotective mechanisms are insufficient to cope with acute injuries, as severe ischemic insult can exhaust the EPO/EPO-R neuroprotective capacity of the brain or the latency of de novo synthesis is too long. Clinical application of EPO should be administered rapidly to provide additional neuroprotection [Brines 2000].