Iron is vital for living organisms because it is essential for multiple metabolic processes to include oxygen transport, DNA synthesis, and electron transport. However, iron must be bound to proteins to prevent tissue damage from free radical formation. Thus, its concentrations in body organs must be regulated carefully. Intestinal absorption is the primary mechanism regulating iron concentrations in the body. Three pathways for intestinal iron uptake have been proposed and reported. These are the mobilferrin-integrin pathway, the divalent cation transporter 1 (DCT-1) [ or natural resistance-associated macrophage protein (Nramp2)] pathway, and a separate pathway for uptake of heme by absorptive cells. Each of these pathways are incompletely described. However, studies with blocking antibodies, observations in rodents with disorders of iron metabolism, and studies in tissue culture cells suggest that the DCT-1 pathway is dominant in embryonic cells and is involved with cellular uptake of ferrous iron, whereas the mobilferrin-integrin pathway facilitates absorption of dietary inorganic ferric iron. Thus, there are separate pathways for cellular uptake of ferric and ferrous inorganic iron. Body iron can enter intestinal cells from plasma via basolateral membranes containing the classical transferrin receptor pathway with a high affinity for holotransferrin. This keeps the absorptive cell informed of the state of iron repletion of the host. Intestinal mucosal cell iron seems to exit the cell via a distinct apotransferrin receptor and a newly described protein named hephaestin. Unlike the absorptive surface of intestinal cells, most other cells possess transferrin receptors on their surfaces and the vast majority of iron entering these cells is transferrin associated. There seem to be 2 distinct pathways by which transferrin iron enters nonintestinal cells. In the classical clathrin-coated pit-endosome pathway, iron accompanies transferrin into the cell to enter a vesicle, which releases the iron to the cytosol with acidification (high affinity, low capacity). Under physiological conditions, a second transferrin associated pathway (low affinity, high capacity) exists which has been named the transferrin receptor independent pathway (TRIP). How the TRIP delivers iron to cells is incompletely described. In addition, tissue culture studies show that nonintestinal cells can accept iron from soluble iron salts. This occurs via the mobilferrin-integrin and probably the DCT-1 pathways. Cellular uptake of iron from iron salts probably occurs in iron overloading disorders and may be responsible for free radical damage when the iron binding capacity of plasma is exceeded. Radioiron entering the cell via the heme and transferrin associated pathways can be found in isolates of mobilferrin/paraferritin and hemoglobin. This interaction probably occurs to permit NADPH dependent ferrireduction so iron can be used for synthesis of heme proteins. Production of heme from iron delivered via these routes indicates functional specificity for the pathways.