Gene mapping techniques to identify gene mutations in humans and animals with phenotypic abnormalities in iron metabolism are providing important insights into the probable molecular mediators of intestinal iron absorption. Positional gene cloning in humans with hereditary hemochromatosis has identified a mutation in a novel major histocompatibility complex (MHC) gene called HFE that is likely to be involved in regulating intestinal iron absorption. In addition, recent observations based on positional cloning strategies in the mk/mk mouse and the Belgrade (b/b) rat rodent models of hypochromic, microcytic anemia have shown that the phenotypic abnormality in iron metabolism is associated with a mutation in the Nramp2 gene. Functional cloning studies in Xenopus oocytes have characterized DCT1 (Nramp2) as an iron-regulated proton-coupled divalent cation transporter. Nramp2 is likely to be the membrane transporter that functions in controlling iron entry across the apical membrane and in the export of iron out of endosomal vesicles. The observation that the expression of both HFE and Nramp2 mRNAs are reciprocally regulated by cellular iron status in Caco-2 cells, a human intestinal cell line, lends additional credence to the notion that these proteins may work in concert to regulate intestinal iron absorption.