Iron is indispensible for life, essential for such processes as oxygen transport, electron transfer, and DNA synthesis. Because of iron's virtual insolubility and potential toxicity, specialized mechanism and molecules for its acquisition, transport, and storage in a soluble, nontoxic form have evolved to meet cellular and organism iron requirements. In vertebrates, iron is transported within the body among sites of absorption, storage, and utilization by the plasma protein transferrin (Tf), which binds iron very tightly but reversibly. Tf is recognized by specific cell membrane receptors (TfR) that are responsible for cellular iron acquisition. Following its intracellular release from Tf-TfR complexes, iron enters functional compartments or is stored in ferritin. In general, cells control iron uptake and storage by elegant mechanisms moderated by interplays between iron-responsive elements (IREs, present in untranslated regions of mRNAs for TfR, ferritin and erythroid 5-aminolevulinic acid synthase [ALA-S]) and iron regulatory proteins (IRPs) that "sense" iron levels in the labile pool. However, some specialized cells evolved mechanisms that can override the ubiquitous IRE/IRP control system. Distinct iron metabolism is best exemplified by erythroid cells, which are the most avid consumers of iron in the organism and obtain Fe exclusively from Tf via TfRs that are transcriptionally "overexpressed". Moreover, in erythroid cells, iron acquired from Tf is specifically targeted to mitochondria where ferrochelatase inserts the iron into protoporphyrin IX to form heme. Cellular functions are disturbed when iron deficiency or excess occurs. Because of the limited ability of the body to excrete excess iron, humans are prone to developing iron overload. One form of Fe overload, hereditary hemochromatosis, is caused by a point mutation in a recently identified gene (HFE) related to major histocompatibility complex class I family. Iron overload also occurs in patients with a genetic defect in copper-containing protein, ceruloplasmin. Since patients with aceruloplasminemia have decreased plasma Fe concentrations, it appears that ceruloplasmin is somehow involved in the mobilization of iron from the cells. J. Trace Elem. Exp. Med.