Erythropoietin (EPO) was originally identified as a hormone produced by the adult kidney to facilitate optimum delivery of oxygen to tissue beds by adjustment of the circulating erythrocyte mass. The cloning of the EPO gene, subsequent production of recombinant protein, and successful introduction into clinical practice for the treatment of the anemia of renal failure is a triumph of biotechnology. However, molecular biologic studies have established that EPO is a member of the cytokine superfamily, with significant homology to mediators of growth and inflammation. Therefore, it is not surprising that additional biologic functions for this protein have been identified. Results from studies have shown that EPO and its receptor are widely expressed in embryonic and adult tissues, including the central nervous system, gut, kidney, muscle (eg, smooth, skeletal, and heart), uterus, retina, pancreas, gonads, and lung. We review the evidence that EPO and its receptor function as a paracrine/autocrine system to mediate the protection of tissues subjected to metabolic stress.