Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia and vascular complications, leading to significant morbidity and mortality. All forms of diabetes are ultimately related to insufficient functional pancreatic β-cell mass to maintain euglycemia. In this context, the promotion of β-cell survival and function is a fundamental issue of direct relevance to diabetes prevention and treatment. Although first identified as a hematopoietic factor that promotes erythropoiesis and erythrocyte survival, an accumulating body of evidence suggests that erythropoietin (EPO) may also exert cytoprotective effects on non-erythroid tissues, including the brain, kidney, blood vessels, and pancreatic β cells. Recent reports have demonstrated the biological effects of EPO on the pancreatic β cells and its potential preventative and therapeutic role in diabetes. This review will focus on the emerging extra-hematopoietic roles of EPO and its potential protective role in diabetes.