The pathophysiology of impaired hemodynamic and nonhemodynamic responses to anemia in patients with coronary artery disease is discussed. In animals, experimentally induced coronary artery disease significantly inhibits the hemodynamic response to surgical blood loss; anecdotal evidence in humans corroborates these findings. Erythropoietic response to surgical blood loss may also be blunted in patients with coronary artery disease. Regardless of whether anemia is the result of a preexisting condition or surgical blood loss, its presence worsens outcomes in patients with coronary artery disease who undergo cardiac surgery. The combination of coronary artery disease and anemia has resulted in acute myocardial infarction as well. Finally, anemia after noncardiac surgery is associated with an increased risk of myocardial ischemia, potentially creating a cycle in which blood loss and myocardial ischemia exacerbate each other. Oral iron replacement therapy after elective cardiac surgery increases adverse events without significantly improving hematocrit and hemoglobin levels or iron stores. Allogeneic blood transfusions are less than ideal, and autologous blood transfusion with erythropoietin administration is only possible before elective procedures. New procedures and medications have reduced the blood loss associated with percutaneous coronary intervention, and minimization of blood loss during percutaneous coronary intervention has potentially major clinical and economic implications.