Erythropoietin (Epo) plays an essential role in the regulation of erythropoiesis by stimulating growth, preventing apoptosis, and promoting terminal differentiation of erythroid progenitors. The Epo receptor belongs to the cytokine receptor superfamily. Epo and its receptor have been localized to several nonhematopoietic tissues and cells, including the central and peripheral nervous systems, endothelial cells and heart. Epo exerts neuronal, vascular and cardiac protection through multiple signaling pathways in different models of tissue and cell injury in vitro and in vivo, such as ischemia, hypoxia, inflammation and oxidative stress. As a result, Epo has been suggested as a possible candidate in the treatment of neurological and cardiac disorders. A better understanding of cellular pathways and molecules modulated by Epo signaling is crucial in determining the potential therapeutic application of recombinant human Epo and may provide further insights in the development of both better synergistic therapies as well as new molecular targets. In this review, we summarize the current knowledge on the signaling pathways by which Epo offers neuroprotection and cytoprotection, signal transduction systems modulated by Epo and negative regulation of Epo signaling in the nervous system.