Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobin-related protein, the receptor also takes up the complex of hemoglobin and the HDL-bound haptoglobin-related protein. This tricks the parasite into internalizing another HDL-associated protein and toxin, apolipoprotein L-I, that kills the parasite. In conclusion, variant human homologous hemoglobin-binding proteins that collectively may be designated the haptoglobins have diverted from the haptoglobin gene. On hemoglobin and receptor interaction, these haptoglobins contribute to different biologic events that go beyond simple removal from plasma of the toxic hemoglobin.