Erythropoietin (Epo), the principal regulator of erythroids progenitor cells, greatly improves neuronal survival. A wide variety of experimental studies have shown that both Epo and the EpoR are functionally expressed in the nervous system and that this cytokine exerts a remarkable neuroprotection both in vitro against different neurotoxicants and in animal models of nervous system disorders. Aim of this review is to summarize the neuroprotective properties of Epo and to outline the molecular mechanisms involved in order to point out the signal transduction pathway which may represent the potential basis for future strategies against neuronal injury.