The two major concerns in the development ofcell-free hemoglobin as a blood substitute (i.e. circulatory retention and oxygen delivery) have been resolved successfully by strategic chemical or genetic modification of the protein. However, the redox reactivity of hemoglobin and its impact on the physiological processes has not been fully understood, nor has it been subject to control by design. This article reviews current research into heme-mediated toxicities that potentially constitute serious impediments to the development of a usable blood substitute.