Oxygen (O2) delivery to tissues plays an important role in determining microcirulatory autoregulatory responses. The balance between O2 delivery by whole blood and tissue O2 consumption likely has evolved based on regulatory processes designed to accommodate the encapsulation of hemoglobin (Hb) within red blood cells (RBCs). The hemodynamic, rheologic, and physical properties of blood, or an alternate O2-carrying solution, can have important consequences for O2 delivery to tissue. The development of acellular hemoglobin-based oxygen carriers (HBOC) requires reassessment of the O2 loading and unloading charactistics of Hb, the effects of altering the rheologic properties of blood, and the impact of these changes on microcirculatory autoregulation and tissue oxygenation. A variety of experimental and clinical studies have demonstrated beneficial effects of HBOCs. However, mechanisms responsible for HBOC-facilitated, O2-dependent autoregulatory changes in the microcirculation have not been completely elucidated.