Transferrin and hemopexin are a specific class of endocytotic systems where the transport protein recycles and the ligands, iron and heme, respectively, are bound to specific membrane proteins to facilitate the intracellular transport of these chemically-reactive, water-insoluble molecules. Hemopexin-mediated heme transport and sequestration of heme to minimize heme-mediated oxidative damage are important in the liver, placenta, eye, regenerating nerves and the central nervous system. Most recent studies using micromolar concentrations of heme-hemopexin as a model for intravenous heme released in hemolysis, trauma and ischemia-reperfusion injury show activation of two signaling cascades for c-Jun N-terminal kinase and Rel/NFkB family of transcription factors. The heme load is not toxic, and cell arrest and induction of protective proteins occurs. The emerging picture is that hemopexin is a cell survival factor leading also to the nuclear translocation of the transcription factors involved in the innate immune response. The hemopexin system is being used to define at the molecular level the pathway from the plasma membrane to the nucleus for protective gene regulation in response to signals from the hemopexin receptor which include a novel role for redox-active copper at the cell surface.