The triad of chronic kidney disease, heart failure and anemia is well described and frequently encountered in clinical practice. While individually these disease states are associated with significant morbidity and mortality, the presence of the triad portends an even worse prognosis. Anemia is prevalent among cohorts of patients with chronic kidney disease and heart failure, indicating that its presence may serve as a central unifying hypothesis to explain poor outcomes in these populations. Observational and interventional trials of erythropoietin-stimulating agents, however, have had variable results on cardiovascular end points. Data are now emerging that suggest that treating erythropoietin deficiency in and of itself may be as or more important than the absolute levels of hemoglobin attained. Future research in this arena must focus on the optimal dose of erythropoietin administered to hemoglobin level achieved that will result in improved cardiovascular outcomes for patients with heart failure and kidney disease.