Heme is a highly abundant prosthetic group of proteins, which are involved in oxygen transport and redox biochemistry. The strong redox reactivity of heme can cause considerable toxicity if intracellular heme levels exceed the homeostatic range. A complex network of scavenger proteins, clearance mechanisms and metabolic detoxification pathways controls heme exposure and ensures save recycling of heme-derived iron. However, in certain disease states such as during hemolysis or rhabdomyolysis extracellular heme levels can reach excessive levels that overwhelm the normal homeostatic control mechanisms. In the presented research we have explored the range of adaptive and maladaptive cellular responses to excessive heme exposure. As a general concept we could link more adaptive responses to the professional heme clearance mechanisms of macrophages such as endocytosis of hemoglobin:haptoglobin complexes. These adaptive changes include enhanced oxidative detoxification and iron handling capacity as well as an altered macrophage immune phenotype with low human leukocyte antigen-D expression. The adaptive response of macrophages is a potential target of positive and negative pharmacologic regulation. As an example we demonstrate that glucocorticoid treatment in vitro and in vivo skews macrophage polarization towards enhanced Hb-heme detoxification and iron recycling, while the anti-malaria drug chloroquine negatively interferes with the protective adaption to Hb exposure. At the other end of the heme response spectrum we characterized the cellular changes during overt heme toxicity and defined their molecular mechanisms. In these studies we defined that excess cellular heme disrupts homeostasis by oxidative reactions and porphyrin mediated impairment of the reparative proteasome pathway, respectively. These heme activities synergistically disrupt cellular protein metabolism and cause cell death.