In the last few years, iron depletion in blood donors has received increased attention. Blood loss results in the depletion of iron stores and both anemia and other effects of iron deficiency have been associated with impairment of physical and mental performance. The intent of this program is to outline the pathophysiology of response to blood loss, the effects of iron deficiency or erythropoiesis and other essential processes, and discuss recent studies in the epidemiology of iron deficiency and replacement in blood donors. The goals of this area of research are to delineate the mechanisms of crosstalk between iron metabolism and erythropoiesis to ultimately inform how the variable predisposing factors influence response to blood donation.