Under normal physiology, human red blood cells (RBCs) demonstrate a circulating lifespan of approximately 100-120 days with efficient removal of senescent RBCs taking place via the reticuloendothelial system, spleen, and bone marrow phagocytosis. Within this time frame, hemoglobin (Hb) is effectively protected by efficient RBC enzymatic systems designed to allow for interaction between Hb and diffusible ligands while preventing direct contact between Hb and the external environment. Under normal resting conditions, the concentration of extracellular Hb in circulation is therefore minimal and controlled by specific plasma and cellular (monocyte/macrophage) binding proteins (haptoglobin) and receptors (CD163), respectively. However, during pathological conditions leading to hemolysis, extracellular Hb concentrations exceed normal plasma and cellular binding capacities, allowing Hb to become a biologically relevant vasoactive and redox active protein within the circulation and at extravascular sites. Under conditions of genetic, drug-induced, and autoimmune hemolytic anemias, large quantities of Hb are introduced into the circulation and often lead to acute renal failure and vascular dysfunction. Interestingly, the study of chemically modified Hb for use as oxygen therapeutics has allowed for some basic understanding of extracellular Hb toxicity, particularly in the absence of functional clearance mechanisms and in circulatory antioxidant depleted states.