Hemolysis occurs in many hematologic and non-hematologic diseases. Extracellular hemoglobin (Hb) has been recognized to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin product in Japan and more recent preclinical animal studies suggest that the natural Hb and hemin scavenger proteins haptoglobin (Hp) and hemopexin (Hpx) have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as red blood cell transfusion, sickle cell disease, sepsis and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma-derived Hp and Hpx as therapeutics for patients with excessive intravascular hemolysis.