With the evolution of fish, systems appeared for the disposal of the hemoglobin (Hb) that was inevitably released from erythrocytes. Thus, a plasma protein that bound free Hb with great affinity, haptoglobin (Hp), evolved from a protease of the innate immune system. In parallel, other proteins appeared (for example, hemopexin and alpha(1)-microglobulin), which bound and mediated the removal of free heme groups. Remarkably, Hp later disappeared in some vertebrate lineages, suggesting that it could also be disadvantageous. In the avian lineage, a soluble protein evolved, possibly from a scavenger receptor, which in some birds seems to have replaced Hp. Among mammals, multimeric forms of Hp appeared independently at two discrete times, suggesting that this form of the protein confers an advantage on the bearer, possibly by improving resistance to infection.