The hormone erythropoietin (EPO) is essential for the survival, proliferation and differentiation of the erythrocytic progenitors. The EPO receptor (EPO-R) of erythrocytic cells belongs to the cytokine class I receptor family and signals through various protein kinases and STAT transcription factors. The EPO-R is also expressed in many organs outside the bone marrow, suggesting that EPO is a pleiotropic anti-apoptotic factor. The controversial issue as to whether the EPO-R is functional in tumor tissue is critically reviewed. Importantly, most studies of EPO-R detection in tumor tissue have provided falsely positive results because of the lack of EPO-R specific antibodies. However, endogenous EPO appears to be necessary to maintain the viability of endothelial cells and to promote tumor angiogenesis. Although there is no clinical proof that the administration of erythropoiesis stimulating agents (ESAs) promotes tumor growth and mortality, present recommendations are that (i) ESAs should be administered at the lowest dose sufficient to avoid the need for red blood cell transfusions, (ii) ESAs should not be used in patients with active malignant disease not receiving chemotherapy or radiotherapy, (iii) ESAs should be discontinued following the completion of a chemotherapy course, (iv) the target Hb should be 12 g/dL and not higher and (v) the risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target Hb <12 g/dL.