Significance: Haptoglobin (Hp) is an abundant human plasma protein that tightly captures hemoglobin (Hb) during hemolysis. The Hb-Hp complex formation reduces the oxidative properties of heme/Hb and promotes recognition by the macrophage scavenger receptor CD163. This leads to Hb-Hp breakdown and heme catabolism by heme oxygenase and biliverdin reductase. Gene duplications of a part of or the entire Hp gene in the primate evolution have led to variant Hp gene products that collectively may be designated “the haptoglobins (Hps)” as they all bind Hb. These variant products include the human-specific multimeric Hp phenotypes in individuals, which are hetero- or homozygous for an Hp 2 gene allele. The Hp-related protein (Hpr) is another Hp duplication product in humans and other primates. Alternative functions of the variant Hps are indicated by numerous reports on association between Hp phenotypes and disease as well as the elucidation of a specific role of Hpr in the innate immune defense. Recent Advances: Recent functional and structural information on Hp and receptor systems for Hb removal now provides insight on how Hp carries out essential functions such as the Hb detoxification/removal, and how Hpr, by acting as an Hp-lookalike, can sneak a lethal toxin into trypanosome parasites that cause mammalian sleeping sickness. Critical Issues and Future Directions: The new structural insight may facilitate ongoing attempts of developing Hp derivatives for prevention of Hb toxicity in hemolytic diseases such as sickle cell disease and other hemoglobinopathies. Furthermore, the new structural knowledge may help identifying yet unknown functions based on other disease-relevant biological interactions involving Hps. Antioxid. Redox Signal . 26, 814–831.