The transferrin receptor is a membrane glycoprotein whose only clearly defined function is to mediate cellular uptake of iron from a plasma glycoprotein, transferrin. Iron uptake from transferrin involves the binding of transferrin to the transferrin receptor, internalization of transferrin within an endocytic vesicle by receptor-mediated endocytosis and the release of iron from the protein by a decrease in endosomal pH. With the exception of highly differentiated cells, transferrin receptors are probably expressed on all cells but their levels vary greatly. Transferrin receptors are highly expressed on immature erythroid cells, placental tissue, and rapidly dividing cells, both normal and malignant. In proliferating nonerythroid cells the expression of transferrin receptors is negatively regulated post-transcriptionally by intracellular iron through iron responsive elements (IREs) in the 3' untranslated region of transferrin receptor mRNA. IREs are recognized by specific cytoplasmic proteins (IRPs; iron regulatory proteins) that, in the absence of iron in the labile pool, bind to the IREs of transferrin receptor mRNA, preventing its degradation. On the other hand, the expansion of the labile iron pool leads to a rapid degradation of transferrin receptor mRNA that is not protected since IRPs are not bound to it. However, some cells and tissues with specific requirements for iron probably evolved mechanisms that can override the IRE/IRP-dependent control of transferrin receptor expression. Erythroid cells, which are the most avid consumers of iron in the organism, use a transcriptional mechanism to maintain very high transferrin receptor levels. Transcriptional regulation is also involved in the receptor expression during T and B lymphocyte activation. Macrophages are another example of a cell type that shows 'unorthodox' responses in terms of IRE/IRP paradigm since in these cells elevated iron levels increase (rather than decrease) transferrin receptor mRNA and protein levels. Erythroid cells contain the highest mass of the total organismal transferrin receptors which are released from reticulocytes during their maturation to erythrocytes. Hence, plasma contains small amounts of transferrin receptors which represent a soluble fragment of the extracellular receptor domain. Measurements of serum transferrin receptor concentrations are clinically useful since their levels correlate with the total mass of immature erythroid cells.